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Antiviral Research and Development Against
Dengue Virus
Bruno Canard, PhD.
bruno.canard@afmb.univ-mrs.fr
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Table of Contents
Part 1. Antivirals 3
A short historical view on antiviral research and therapies 3
Lessons learned from recent viral diseases and pandemies 3
The methods used to discover antivirals 4
Infected cell assays 5
Knowledge-based methods 5
The source of anti-infectious molecules 6
Why has natural product screening been neglected in antiviral research ? 8
Challenges associated with natural products in antiviral research 8
What is a validated antiviral target ? 9
Animal models 9
Patient cohorts and clinical trials 10
Frequent arguments about antiviral therapy feasibility 10
The introduction of dengue as a druggable disease 11
Diagnostics, and what does it tells us for antiviral therapy ? 11
Current treatment 11
Part 2. Dengue 13
Preamble 13
The Dengue Virus 13
The DENV targets for antiviral research 13
Overview of genome organisation 14
Overview of the DV particle and DV proteins as targets for drugs 14
The structural proteins 14
The Non-Structural proteins 15
RNA structures 17
The dengue validated targets 17
The cellular targets for antiviral research against dengue 18
siRNAs as tools and/or therapeutic agents 19
Response modifiers 20
Monoclonal antibodies 21
Mechanical devices 21
Part 3. Academic and academy-associated research centers 22
Part 4. The current industrial network of AV discovery 31
Part 5. Mapping the dengue drug design effort and needs 38
Annex 1. References 42
Annex 2. Patents 43
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Part 1. Antivirals
A short historical view on antiviral research and therapies
The first significant successes of anti-infectious disease treatments originated from the discovery and
use of antibiotics. The discovery of many viruses preceded largely the discovery of the first antiviral
molecule, which occurred at least 40 years after that of penicillin in 1928. The first documented
description of an antiviral molecule, that of 5-iodo-2'-desoxyuridine, occurred in 1959. It was
discovered active against Herpes ophthalmologic infections and followed by a series of related active
molecules. The fight against herpes was the perhaps the earliest and most significant driving force of
antiviral research. Herpes was the only significant viral disease for which all technical elements and
systems required to develop an antiviral molecule first became available (i.e., in vitro infected cell
systems, animal models, chronically infected patients,…). The antiviral drug field came of age in the
next decades with the first antiviral molecule finding its way to the clinic: Gertrude B. Elion
discovered acyclovir(2) a scientific breakthrough for which she was later awarded the Nobel prize in
1988. The subsequent emergence of AIDS in 1981, and the following pandemics drastically changed
the field of antiviral research, allowing the widening of concepts, technical developments, rules, and
business.
Lessons learned from recent viral diseases and pandemies
HIV and HCV: chronic invaders
The most important lesson comes from the following great achievement: it is possible to control a
chronic infection of a very sophisticated virus, such as HIV, that hides inside the chromosomes of the
infected cell. Although the victory is not total yet, it has profoundly changed the fate of the pandemic
victims, at least in western countries. After being inspired by other research fields, anti-HIV research
has “infected” other field of antiviral research and will continue to do so. Remarkably, after the
identification of HIV, the control of HIV through antiretrovirals originated from a collective effort on a
wide variety of scientific and medical fields, including efficient transfer from academia to the
corporate world. More recently, hepatitis C virus (HCV) research is now boosting the antiviral
chemotherapy field. Viral polymerases and proteases are targets par excellence, validated by the use
of inhibitors against HIV reverse transcriptase and protease, hepatitis B polymerase, and herpes virus
polymerase. Anti-HCV protease and polymerase inhibitors are in various stages of clinical trials.
Novel targets and cognate inhIbitors are adding to the list, such as the HIV integrase, and the HCV
NS5A.
HCV (genus Hepacivirus) and DENV (genus Flavivirus) belong to the same viral family Flaviviridae
sharing similar genome organization and replication strategies. Initially, research conducted on dengue
virus (DENV) was the actual starting and inspiration point for HCV research, when it became known
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that HCV had a flavivirus-like genome. Presently and conversely, knowledge and strategies gained
from the successful drug discovery and design process against HCV can now be translated back to the
DENV research field.
SARS and Influenza (H5N1 and H1N1): “hit and run” viruses
The SARS pandemic was due to a novel coronavirus which emerged in 2003 from China. The virus
took the world by surprise as coronaviruses were not known to cause life threatening pathologies.
Coronaviruses were clearly neglected viruses from the scientific and the medical/veterinary point-of-
view. The pandemic revealed blatantly our unpreparedness to such a problem: point-of-care in
hospitals crowded with contagious patients, high toll for clinicians, tracing secondary contacts of taxi
drivers and plane passengers, etc…The pessimistic say that nowadays viruses travel around the world
in 3 days. The optimistic say that social networks and cell phones make information travel much
faster. Perhaps the true challenge is elsewhere: making people believe and adhere to an “official”
information, as exemplified with the recent H1N1 crisis and the unsuccessful vaccination campaign. In
any case, this crisis has been the best advocate for antivirals as a complementary strategy to
prEvention and vaccination.
In the case of influenza, the size of the market has been the main booster of anti-influenza drug
development. This includes the availability of patients for clinical trials, and the fact that a potential
devastating pandemic would undoubtedly provoke stockpiling of antivirals in the time-window into
which an appropriate vaccine would available. Advice to stockpile anti-influenza drugs has been
recurrently advertised, mostly after 1995 when the 1918 spanish influenza strain genome was
published(8). well before the H5N1 and the H1N1 fear hit the world.
These two viruses do not produce chronic infections. These types of virus produce an infection
(unnoticed, mild, or acute) which resolves with virus clearance. This transient nature of the infection
has long been a problem to design an efficient therapeutic answer. Indeed, there are too many
unpredictable parameters to build a drug-design program based on traditional planning and funding
approaches. The two biggest problems are that it is impossible to evaluate precisely the market (and
invest accordingly), and that there is an unpredictable number of patients available for clinical trials.
The instructive aspect of these pandemics, however, is that they greatly contributed to re-shape
antiviral research at large (how can we anticipate? how money is going to be invested? ). These recent
crises have shaped considerably the grand public opinion towards the necessity to have broad-
spectrum anti-influenza drugs ready.
The methods used to discover antivirals
The original method of discovery of antivirals was partially a knowledge-based method, centered
around nucleobases and nucleosides (eg., uridine derivatives mentioned above against Herpes), known
to be used by viruses for their replication. The advent of AIDS and the discovery of non-nucleoside
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reverse transcriptase inhibitors opened the era of large-scale screening, which is entirely a trial-and-
error procedure, not based on previous knowledge. Millions of compounds are tested as fast as
possible (using high throughput screening (HTS) techniques), and only those showing activity are
selected.
Infected cell assays
In both cases (Herpes and AIDS), infected cell cultures provided the antiviral read out, before purified
targets were available and could be used. In these assays, compounds are tested individually to see if
they either cure an infected cell, or protect it from infection, pathogenic effects. The process is simple,
and relies on a cell culture system able to support virus growth. Not surprisingly, the discovery of
antivirals parallels the establishment of a robust infected cell based assay. When this was difficult or
even not possible (eg., HCV), the use of sub-genomic replicons or surrogate viruses has nevertheless
allowed drug discovery and design. There are now a wide variety of assay systems specific for each
virus. Robust dengue infected cell assays are available, highly efficient in terms of characterizing the
potency of a drug candidate. One significant disadvantage is the cost associated with cell culture
reagents and facilities, especially in low income countries. However, this method has an impressive
record of success compared to other methods.
Knowledge-based methods
The general trend is to reduce this trial-and-error approach and inject knowledge as much as possible
in the selection process so as to reduce costs and increase efficiency.
Computer-aided structure activity relationship (SAR) studies facilitate a responsive and efficient
management of research results and programs. Drug-resistance must be considered as part of the drug-
design process, as drug resistance mechanisms are being increasingly characterized and drug
combinations optimized, in order to avoid or delay resistance. The first large-scale effort to discover
anti-DENV drugs is to be credited to the Novartis Institute of Tropical Diseases (Singapore), who
conducted a complete screen of their proprietary chemical library against the DENV protease domain
from non-structural protein NS3 (see below).
Knowledge-based methods differ from classical cell based screening techniques in that they use
screening or discovery systems characterized at the molecular and sometime atomic levels. The
discovery system represents or approximates a given step of the virus life-cycle. The knowledge
associated with the system reduces the number of putative targets, and is supposed to provide directly
a mechanism of action of the compound or candidate drug. Examples of such systems are purified
enzymes used directly in the drug discovery test. It is expected that inhibition of the enzyme by a
compound in a test tube will mimic inhibition of the enzyme in the context of a viral infection. This is
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of course not granted. For a good enzyme inhibitor, the most frequent reasons of failure to inhibit a
virus in a cellular context are:
• The compound does not penetrate inside the cell.
• The compound is rapidly degraded/metabolized/transformed into an inactive compound
• The compound is toxic and of poor selectivity, ie., when used in a cellular context, the
compound will kill the infected cell and any direct effect on the virus is not apparent.
Many compounds can be selected as good inhibitors of a viral enzyme. However, the majority will fail
to convert into a candidate drug for the above reasons.
However, the main advantages of the method are:
• it discovers both a compound and its target at the same time.
• Currently, increasing general medicinal chemistry knowledge allows a better pre-screening of
compounds that have potential, ie., chemical libraries used as the source of molecules are each
day better in terms of containing “drug-like” molecules.
The future is the integration of both cell based assays and knowledge-based methods, to reduce the
time involved in i) finding the target at the molecular level, ii) having a trustable molecular/atomic
model to go quickly into hit-to-lead development by medicinal chemistry.
The source of anti-infectious molecules
Before their antiviral properties are discovered, antiviral chemicals or molecules either exist physically
somewhere in the world (and are selected or discovered), or they do not exist, and are invented and
subsequently synthesized. For molecules having a physical existence, they are either owned by
someone, and generally organized in a chemical library (or repository), or they are in the wild, in
plants, marine organisms, insects, etc…The issue of final ownership (ie., of a discovered molecule
having interesting properties) is then much more complicated.
This is an important distinction that has wide implications in drug discovery, from the ease of
discovery to the final ownership and availability to patients. The source of antiviral molecules is
indeed a key issue, particularly for dengue, for two main reasons:
• The cost of a drug is going to be a main issue because dengue occurs majoritarily in low
income countries.
• Although the low income dengue-afflicted countries generally do not have screening and drug
design facilities, most of the potential natural sources of drugs (mostly plants) are located in
these countries.
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Chemical libraries
The availability of large collections of pure compounds that can be handled, tested, analyzed and
whose compounds can be re-ordered has considerably evolved over the last decades. These large
collections were initially exclusively found in large pharmaceutical companies. Over the years, these
companies had accumulated compounds, assays, and know-how. The situation has drastically changed
over the last decade, mainly because robotics and bio-chemo-informatics have penetrated academic
modest-in-size labs and research structures. It has long been argued that screening was “an industrial
job” best accomplished in a corporate setting, an observation that was true to a certain extent, because
sophisticated robotics, engineering know how, and manpower was more easily mobilized there. The
decreasing cost of screening-associated technology, the diversity of the screening needs (targets,
pathways, organisms, pathologies,…), as well as the advent of proteomics and siRNAs (see below) has
done that many labs have their own screening facility, often small scale, for the defined process or
biological system they are studying. Likewise, many service centers and small companies are able to
propose screening as a service. Many large chemical libraries can be bought, several million pure
compounds are physically available to any purchaser. For a lab or company screening compounds
against a given virus or biological system, the problem is more to have original libraries. Indeed,
unique libraries that are not freely available minimize risks for a lab of being competed out, and
simplify the intellectual property of discovered molecules.
It looks that the tendency of screening very large collections of pure molecules is declining. This may
be due to the fact that methods to pre-screen virtually these collections have evolved to a point where
more focused libraries can be built, and small focused screens can be conducted on these “enriched”
libraires. Likewise, the increasing availability of atomic models (mostly crystal structures) of targets
make this preparation of enriched libraries much easier.
It is certainly too early to draw conclusions about the justification of great hype and faith on HTS
during the last two decades. There is a consensus to state that the number of drugs reaching the market
has decreased sharply in this period of time, relative to previous periods where drug discovery relied
much more on the screening and discovery of natural compounds (see below). The reasons are
certainly more complex than a mere wrong direction of the whole drug discovery and design world.
However, for a number of reasons, discussed below, the source of antiviral molecules will undoubtedly
evolve towards more screening from natural resources, blending with a great deal of experience in
high throughput techniques and medicinal chemistry expertise acquired in these past two decades.
Natural sources
Plants have been the traditional (and almost exclusive) source of active substances for most therapies.
At the present time plants are the indirect or direct source of ~ 50 % of approved drugs. Anticancer
drug research has been a leading force in natural product research and screening processes. From the
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1940s to 2007, 73% of the 155 small molecules approved as anticancer drugs were from natural
origin, directly derived from a natural product, or inspired by a natural product(4). To put antiviral
research in perspective, in the 1940s, there was not a single molecule known having an antiviral effect,
and the discovery and isolation of the first human viral pathogen was only 13 years away (Yellow
fever virus, in 1927). It is not surprising that the concepts of natural product screening, established for
cancer and inadequate for antiviral screening, had not entered the antiviral research field.
Why has natural product screening been neglected in antiviral research ?
First, many plant extracts are cytotoxic, a desired property for an anti-cancer drug. However, an
extract that kills the cell does not allow the monitoring of virus growth or inhibition. One has to use
extracts that are non-cytotoxic. By jeopardizing selectivity (ie, the ratio of inhibitory concentration for
the virus over toxic concentration for the cell), cytotoxicity has stopped many compounds or extracts
on their way towards antiviral pre-clinical trials. Second, when non cytotoxic crude extracts are used,
almost all of them exhibit antiviral activity. This antiviral activity is due mainly to compounds that
have no interest as antiviral drugs. These compounds are a wide variety of polymers, polyphenols, and
tannins. Third, if one avoids the above traps, screening natural extracts yields a lot of true inhibitory
molecules that are already known and characterized (and will fail in a composition-of-matter patent),
and have low potential for chemical modification into a useful and unique pharmacophore.
As consequence, during the past twenty years, the advent of combinatorial and parallel chemistry
coupled with high-throughput screening techniques has led to a decreased emphasis on plants (or
microbial, marine extracts) as a compound source. Nature has continued to inspire chemists and drug-
designers during the development of natural product-based compounds (such as antiviral nucleoside
analogues), but no natural product has actually been approved as an antiviral drug out of the 35 drugs
approved up to 2002. The trend seems to change as at least 8 natural products are since in clinical
trials in the field of virology (HIV and HCV), such as Calanolides A and B, DCK(PA-334B), 3,5-Di-
O-caffeoylquinic acid, MX-3253, 4-Methylumbelliferone, Bevirimat, Sho-shaiko-to H09, and
Sutherlandia frutescens(6).
Challenges associated with natural products in antiviral research
Whilst natural products as a source of drugs were falling out of favor of pharmaceutical companies,
the interest of this source was growing dramatically in countries were these resources are located, ie.,
mostly low income countries of the developing world. The main incentive was the adoption of the
Convention on Biological diversity, enforced in 1993. The challenges associated with this resource are
technical and policy issues(3).
On the technical side, the difficulty to deal with natural extracts has been developed above. There are
now an increasing number of methods reporting how to prepare an extract suitable to specific needs,
including antiviral research. Here also, technology has helped in the preparation of extract libraries
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pre-cleaned from unwanted substances described above (tannins, polymers, …). A second difficulty is
the variability of the source. Re-collection of the same plant may not give the same chemical
composition of an extract (different season, different development stage, misidentification, etc…). The
third difficulty is the resupply problem, particularly in large quantities. Over-harvesting may occur,
although it is sometimes possible to find alternate sources of the compound (plant cell culture, other
species, etc…). Last, isolation, re-synthesis of hemi-synthesis can be challenging, although science,
technology, and know-how are advancing faster than policy issues. However, natural products
collection and assays are located in the developing world, which is increasingly involved in finding
primary activities of an extract. When the next step in engaged, large pharmaceutical companies
having down-sized their natural product departments are not often ready to carry on. There is an
increase need to build intermediate/small dedicated structures in the corporate of academic world.
The policy issues associated with biodiversity exploitation address mainly the location of study of the
natural product collection. Authorizations, contracts and agreements can vary from extremely slow to
quite easy and diligent(3).
What is a validated antiviral target ?
A “validated target” is a cellular or viral component (protein, membrane, macroassembly,…) which,
when bound to a drug, leads to virus control (growth inhibition, elimination, virostatic,…) in the
infected cell, and hopefully, in patients eventually. Thus, any protein viral protein is not a validated
target, for example if, when inhibited or destroyed, the virus can still grow using and alternating
pathway compensating for the loss of its inactivated protein. Regarding the host cell proteins that can
be used as targets (ie., cellular proteins required for virus growth), blocking those proteins must be
both safe enough for the cell (ie., shown no toxicity at least for the uninfected cell) and the virus must
be unable to use an alternate protein compensating for the unavailability of the blocked protein.
Typical example are viral receptors. In many instances (eg., HIV), there are several cellular receptors
for the same virus. Blocking one receptor forces the virus to rely on other receptors, sometimes with
little effect on viral growth.
Animal models
In the case of dengue, the best animal model is the AG129 mouse, which has however a number of
drawbacks such as low and short viremia. Efforts are ongoing, mainly in academic labs to improve this
model. Surrogate systems exist that do not have these drawbacks (eg., the flavivirus Modoc virus),
and chimeric dengue/modoc viruses may yield interesting systems. Also, other animal systems are
being evaluated (golden hamster, macaques, …) with the increasing variety of dengue strains
available.
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Patient cohorts and clinical trials
The first large scale clinical trial has been conducted in Viet Nam (chloroquine), and another is
ongoing (see below, the Roche nucleoside analogue). This indicate that there is a sufficient and
sustained number of patients to go into clinical trials for any promising molecule. Other sites for
clinical trials will undoubtedly see the light, either in Asia or South America.
Frequent arguments about antiviral therapy feasibility
The most common argument opposed to antiviral therapy is that it would occur too late, ie., when the
viremia is already declining, low, or the virus cleared.
Diagnostic tests to rapidly detect DENV infection at an early stage (ie., early viremia) are currently
available (see below), and it has been demonstrated that there is a direct correlation between high viral
load and the development of the more severe, life-threatening form of dengue disease. The higher, the
worst. Thus, a drug reducing viral load at an early stage would potentially prevent DF and DHF/DSS.
Dengue viremia is short, being detectable only shortly before or concomitant to the onset of fever and
lasts four to five days after. The ability to rapidly diagnose dengue disease is thus key to the successful
implementation of antiviral chemotherapy.
Although virus may not be detectable in plasma, viral replication may be occurring in other cell
reservoirs, tissues, and body compartments where an antiviral drug could reach and target them. For
example, it is suspected that in addition to plasma leakage, the life-threatening DSS may involve
damage of organs such as the liver (DSS associated hepatitis) or heart (DSS-associated
myocardiopathologies).
In endemic outbreaks, prophylactic mass treatment around index cases would be essential. Rapid
diagnostics would detect infected yet asymptomatic people. Another as yet unevaluated consequence
of prophylactic treatment and decrease of viremia should appear in the vector-infection pattern.
Decreasing viremia in humans should result in a decrease in infected vector population and thus
impact on the transmission chain. Therefore, an efficient and safe drug, delivered early in the course of
dengue disease, should not only save lives but also curb potential epidemics.
An on-the-shelf drug allows a rapid response in the case of a sudden outbreak, and should not require
cold storage, an advantage for use in developing countries.
Lastly, in other deadly viral systems (Monkeypox virus as a surrogate system for Smallpox virus), 24h
post exposure prophylaxis with the drug cidofovir has been shown to significantly reduce mortality of
monkeys challenged with a lethal monkeypox infection, compared to 24h post exposure vaccination
which had no effect(7).
The second most common argument is that dengue occurs in low income countries where there is no
sizeable nor predictable market. Up to now, it is true that the common models of drug development
rested on analysis of an existing market, and financial planning and investment accordingly. It is
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apparent that this system will continue as it is for diseases that have a sizeable and predictable market,
most often chronic viral diseases. However, new business models have to appear for pandemic viruses
threatening many parts of the world simultaneously, irrespective to frontiers, the SARS –CoV and the
pandemic Flu being appropriate examples. In the case of dengue, the increasing incidence concerns
more and more countries, so a global response would be welcome. In addition, a potential dengue
drug would now cross the line of profitability. The number of companies interested in dengue
antivirals has increased sharply these past five years, and is still expected to increase.
It is also possible, at a very early stage in drug-design, to guide research on molecules that will be
cheap to produce. Cost-effectiveness is a crucial issue for this still poverty-linked disease. Cost-
effectiveness can be achieved by selecting as early as possible appropriate, easy to synthesize
chemical scaffolds, or by mining on active natural compounds (as discussed above) and selecting
those that represent major chemical constituents of appropriately available plants.
The introduction of dengue as a druggable disease
Dengue fever is not enough recognized as a major viral disease in terms of public health and economic
burden, although the situation is currently changing. The Jain PharmaBiotech report on “Antiviral
Therapeutics: Technologies, Companies, and Markets (February 2010)” mentions dengue within only
2 pages out of >450. However, the more aggressive expansion of the disease in the world, as well as
the emergence of a market, are attracting attention of novel actors in the field from both academic and
corporate world. There is no vaccine nor treatment available, and projections are that both will be
available approximately at the same time, ie., within ~5 years.
Diagnostics, and what does it tells us for antiviral therapy ?
There is no possible antiviral therapy without reliable diagnostics, and, in the case of dengue, rapid
diagnostics. In its early stages, dengue fever is often confused with other tropical diseases, which may
lead to inappropriate therapy. Since it is expected that cutting viremia as early as possible might result
in less severe dengue disease, dengue infection markers that parallel viremia are the best that one can
expect. This expectation is becoming reality with the presence and detection of dengue NS1 in
plasma/serum of patients though ELISA technology, preceding the appearance of dengue-reactive IgM
in the first days of illness.
Current treatment
The treatment is essentially supportive, and there is a very important challenge in estimating the
severity of the disease as early as possible. Indeed, unlike most other diseases, a key stage of the
disease is the patient’s defervescence during which increased vascular permeability may appear whilst
viral load and body temperature (fever) are declining. Close surveillance of this phase, which may
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need intravascular fluid replacement and maintenance of good haemodynamic stability, is crucial for
disease outcome.
Disease surveillance and characterization will certainly be key in the implementation of an effective
and appropriate antiviral therapy. Much is to be learned about targeting the virus in specific tissues
(liver, heart, brain,…) with appropriate antivirals in the future. The increasing knowledge about the
host response to a dengue infection is expected to bring most useful care and support to dengue
patients, whereas knowledge of DENV components and life-cycle will eventually lead to efficient
antivirals, most probably in combination with those targeting cellular targets (see section “The cellular
targets for antiviral research against dengue”).
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Part 2. Dengue
Preamble
There are a number of recent high quality scientific reviews about dengue, the DENV, and anti-dengue
drug design. Amongst the most complete and relevant are:
• Dengue (2008) Tropical Medicine: Science and Practice, Vol. 5, Scott B. Halstead Editor,
Imperial College Press.
• Gubler, D., Kuno, G., and Markoff, L. (2007) Flaviviruses, in Fields Virology, Vol.1 Fifth
edition, LWW, Knipe DM and Howley PM, Eds.
• Noble, C. G., Chen, Y. L., Dong, H., Gu, F., Lim, S. P., Schul, W., Wang, Q. Y., Shi, P. Y.
(2010) Stategies for the development of DENV inhibitors, Antiviral Research, 85, 450-462.
The reader will find a lot of references in these documents. For the sake of clarity, only key references
and references that may not be in these documents will be cited in the following text. Much of the
work has been performed in the laboratories mentioned in the academic labs and center list below.
Lastly, the list of patents sorted by year in annex 1 is also a valuable source of information.
It is not the intention of this document to re-formulate what has been excellently written by expert
colleagues in the field. Rather, the purpose of this document is to connect many known or emerging
facts about anti-dengue drug design, evaluate where we presently are, what and where are the needs
and challenges to promote and sustain an active anti-viral drug design field.
The Dengue Virus
The DENV targets for antiviral research
Flavivirus and Flaviviridae research has led to the characterization of an increasing number of viral
encoded proteins and enzymes, including envelope and capsid proteins, polymerases, helicases and
proteases. Processes involved in the entry of DENV into cells (virus-receptor binding, E protein
conformational changes, virus internalisation and membrane fusion) are being more and more
understood at the molecular level. For DENV whose RNA genome is decorated by a type-1 cap
structure, enzymes involved in cap formation such as the RNA triphosphatase, guanylyltransferase
(still unknown) and methyltransferase are additional potential targets. Considerable progress has been
made in their characterization. Chemical libraries from natural and synthetic origins can now be
screened against these novel pathways and targets.
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Overview of genome organisation
The genome organisation is that of single positive strand RNA genome virus, ie., it is similar to a large
cellular mRNA molecule. The genome is approximately 11 kb in size, bears a type I cap structure at its
5’-end, and lacks a 3’-polyadenylate tail. The long open reading frame encoding a large polyprotein is
flanked in 5’ and 3’ by untranslated regions (UTRs). The latter carry a number of cis-acting signals
(stem loops, conserved sequences, …) required for viral replication, and possibly RNA capping. There
are complementary sequences in these UTRs that are thought to be responsible for cyclization of the
genome, which is essential for replication.
Overview of the DV particle and DV proteins as targets for drugs
Flavivirus are enveloped viruses having two outer membrane proteins, the envelope (E) and the
membrane (M) processed from the precursor prM. The genome is thought to be wrapped/associated
with the capsid protein C. A single polyprotein is translated from the genome, and the former is
cleaved by a combination of cellular proteases and a viral serine protease made of NS2B and NS3
(protease N-terminus domain).
Figure 1. The DENV (+)RNA genome and it co-linear polyprotein.
Proteolysis yields ten proteins, the three structural proteins (C, prM, and E) and the seven
nonstructural (NS) proteins involved in genome replication and capping (NS1, NS2A, NS2B, NS3,
NS4A, NS4B, and NS5). Some of these NS proteins also participate in pathogenesis and counteract
the innate immunity of the host cell.
Replication of the viral genome does not occur freely in the cytoplasm. Instead, there is an extensive
intracellular membrane re-arrangement in the infected cell, with various observable cell substructures
containing most NS proteins organized along the virus replication cycle.
The structural proteins
The M and E proteins have been considered so far as drug targets. The E protein is endowed with a
dual function : to recognize cellular receptor, and to fuse the viral membrane to cellular endosomic
membranes. Five receptors have been found to be involved in binding to E : DC-SIGN, L-SIGN, the
high affinity laminin receptor, the mannose receptor, and GRP78. E is an attractive target because
theoretically, an antiviral molecule binding and impeding attachement would act before infection or
spreading the virus to yet-uninfected cells. In the RNA virus antiviral world, there are several
examples of such inhibitors targeting early phase of the viral life cycle : that of T20 (a fusion inhibitor
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corresponding to the C terminus ectodomain of gp41) in anti-HIV therapy(1) and that of Pleconaryl, a
small molecule enterovirus capsid binder(5).
Several disadvantages are associated with these drugs : peptide inhibitors are delivered intravenously,
and picornaviral capsid binder elicits quickly drug resistance. Parenteral delivery is a serious
drawback for any dengue drug which would preferably be delivered with limited hospitalization and
epidemic settings, and drug resistance might not be such a crucial issue as it is for chronic viral
infections.
The dengue E protein crystal structure is known. E belongs to class II fusion proteins. Upon binding to
a receptor and endocytosis under a trimeric form, the acidic environment of the endosome induces a
structural re-arrangement yielding fusion of cellular and viral membranes. Theoretically, a similar
strategy as that of HIV and T20 could be followed. Crystal structure study of a E fragment has
revealed a pocket that could be used for antiviral drug-design. The crystal structure of the prM protein
bound to E (prM-E heterodimer) is known, opening avenues for drug design. The structure of the
capsid protein C has bee elucidated in solution. The E protein is the most obvious target for
therapeutic monoclonal antibodies (see below).
The Non-Structural proteins
Out of the seven NS1-to-NS5, only NS3 and NS5 have been considered so far as drug targets, not only
because they are essential to virus growth but also because they exhibit enzyme activity, which is a
plus regarding drug screening. The role and structure of NS1 is unknown. It is a soluble protein
detected very early during infection, but has received little attention so far as an antiviral target. NS2a,
NS2b, NS4a, and NS4B are membrane –associated proteins believed to anchor and regulate the
replication complex during the virus life-cycle.
• NS3 (69 kDa) carries two functional domains, a N-terminal serine protease(~170 aa), and a C-
terminus helicase/RNA triphosphatase (~440 aa). The protease domain is inactive alone, and
needs the presence of 40 aa of NS2b bound to form a protease active site. The NS2b/NS3
protease has been the first dengue protein target actively used in drug design programs.
Tragically, the crystal structure reported in 1999 for this domain was fraudulent, and the
original article retracted in 2009. Two complementary approaches have been followed to
discover antivirals based on the inhibition of this enzyme. The first approach has been the
screening of a large chemical library (1.4 million compounds by NITD alone, see on the list of
companies below) and the second approach has been to design peptidomimetics, an approach
which has also been followed in the case of HCV. So far, the relatively flat topology and the
charge repartition of the NS2b/NS3 protease active site is believed to account for the difficulty
of finding potent compounds. However, such difficulties have also been mentioned many
times for the HCV protease, but patience and obstination have finally payed off with the
15
discovery of potent HCV NS3 protease inhibitors.ne other potential problem is that the
protease domain might be regulated by its C-terminus fellow helicase domain, as different
conformations of the full-length NS3 have been reported. A great deal of knowledge has been
accumulated and published on this protease, and progress are still accumulating in this field,
so the future may be more favorable, perhaps in combination with other dengue drug/target
pairs. The NS3 helicase domain is also an interesting target because it contains features unique
to flaviviruses, such as Domain III. However, drug discovery and design against this enzyme
has proven challenging for several reasons such as poor helicase activity in vitro, a too-open
ATPase active site, and the absence of obvious pockets able to accomodate small molecule
inhibitors. Several HTS assays have nevertheless been developed, but so far, no convincing
small molecule inhibitor has been reported, a situation paralleling that of HCV helicase.
• NS5 is the largest and most conserved and most conserved dengue protein. NS5 is a 900
amino acids protein (~100 kDa) carrying the enzymatic activities required for RNA capping
and synthesis of the dengue RNA genome. The NS5 N-terminal domain has been shown in
2002 to be a 2’O Methyltransferase (MTase) through crystal structure analysis, and later, the
N7-guanine MTase activity was also demonstrated to be embedded in the 260 amino acid
fragment. The NS5 C-terminus domain has been shown to carry RdRp activity in in vitro
assays, and its crystal structure has been determined in 2007 simultaneously to that of West
Nile virus. The full structural picture will be completed when the full-length NS5 crystal
structure is going to be available. In a parallel to HIV and HCV drug design programs, the
knowledge of a structure of a ternary complex made of NS5/RNA/NTP would certainly add
excitement to this growing active field. Indeed, « naked » polymerase structure used in drug
discovery often point to inhibitor compounds that are sub-optimal when assayed against
replication complexes. Two main types of inhibitors have been described for polymerases.
The nucleoside analogues are substrate mimics that, once activated and incorporated into the growing
RNA chain, stop RNA synthesis, hence they are called « chain terminators ». To do so, nucleosides
must be phosphorylated by host cell kinases up to the 5’-triphosphate state, then compete with natural
substrate selectively at the viral RNA polymerase active site. This concept has met with impressive
success in the case of HIV and other viral DNA polymerases. In that case, ie. DNA polymerases, the
5’-triphosphate nucleoside analogue is competing with micromolars of natural dNTP substrates. In the
case of viral RNA polymerases, the problem is complicated by the fact that analogues have to compete
with intracellular millimolar concentrations of NTPs. Large scale screening of these analogues relies
on using libraries focused on the nucleoside motif. Because of the required activation through 5’-
phosphorylation, screening can only be performed on infected cell cultures.
16
High throughput screening methods have introduced the novel concept of non- nucleoside analogues,
ie. random chemical structures of small organic molecules able to bind specifically to a viral target.
The major challenge for these inhibitor ligands is to target a conserved pocket not so prone to
mutation, otherwise, drug resistance will occur very quickly though rapid appearance of mutations.
For dengue, it remains to be evaluated whether or not drug resistance is going to be a significant
problem. Or these compounds, initial large scale screening can be achieved using subgenomic
replicons, infected cells, and purified enzymes (see above « the methods to discover antivirals »).
NS5 may also play a role in pathogenesis, so its targeting may hit two birds with a single stone. NS5
has been reported to interact with STAT2, perturbate interferon signaling, and its traffic within the
nucleus of the infected cell is far from being understood.
RNA structures
The dengue genome is a single stranded RNA molecule of positive polarity. However, the replicative
form of dengue RNA is not a single linear molecule but rather, a cyclic or dimerized genome. This
special genomic RNA organization proficient for replication carries many highly ordered secondary
and tertiary structures ensuring proper regulation of dengue RNA synthesis. Most of these RNA
structures are located in the 5’ and 3’ untranslated regions. For example, the TIA-1 and TIAR antigens
have been identify to interact with 3’-stem loop structures and inhibition of their interaction has an
antiviral effect in infected cells (see patent list). Phosphorodiamidate-linked morpholino
oligonucleotides (PMOs) have also been shown to target efficient RNA stem-loop structures (see
patent list, 2007). Since they are unique to the viral RNA genome, and since the scientific field of
small RNAs is booming, it is almost certain that these RNA regions contain a significant potential for
drug discovery and design, yet to be addressed and validated.
The dengue validated targets
Presently, there are no drugs against dengue in the clinic. Therefore, what we call a validated target is
only derived by analogy to other viruses for which drugs have proven to be effective. Herpes and HIV
have been the drug-design founding viruses. Now for DENV, HCV is fulfilling this role. Recent data
presented regarding a nucleoside analogue, although toxic, have shown that the NS5 protein is a
validated target (see compound NITD008). The validated targets are thus the RNA-dependent RNA
polymerase and, by analogy to HCV, the protease. More recently, the HCV NS5A protein seems to
emerge as a very interesting target, but NS5A does not have an equivalent in dengue, so far.
Conversely, the dengue RNA genome is capped, and the DENV genome encodes most of its own RNA
capping machinery. This is not the case for HCV, which does not rely on RNA capping for gene
expression. The RNA capping enzymes of dengue so far await validation in an animal model both at
the level of efficiency, and toxicity. Indeed, it is not known if the abundance of cellular MTases will
17
cause a specificity problem, ie., if it will be possible to design an anti-dengue MTase inhibitor having
non-significant toxicity effect through co-lateral inhibition of host cell MTases.
The cellular targets for antiviral research against dengue
The host cell is actively involved at many levels during DENV infection, either at the level of innate
immunity and counteraction thereof, or providing co-factors and template for replication of the virus.
In theory, any of the cellular proteins involved in DENV life cycle is a potential target for antiviral
therapy. The strategy may differ if the cellular protein has to be activated or inactivated. Several
proteins belong to the former case, such as RNase L involved in innate immunity. In the latter case, the
protein might be actually used by the virus to promote its own growth, and the cellular protein will
have to be inhibited or this promoting activity inactivated somehow. As an example, this could be the
case for furin-like proteases and signal peptidases initiating the dengue polyprotein processing. A third
category of cellular targets is that of cellular proteins involved in pathogenesis and not viral replication
directly. These proteins certainly represent interesting targets, but presumably, an antiviral drug effect
would have to be fine-tuned to avoid complete repression of these host defense factors, yet conserve a
sufficient effect to dampen the excessive host response responsible for pathogenicity.
In any case, the two main pre-requisites for host factor inhibitors are that the cellular protein or
macromolecule can effectively be used as a template for drug design (ie., acceptable druggability) and
that, when used, there is a non-significant or acceptable level of cytotoxicity.
There are a number of known cellular proteins and pathways that exert an anti-dengue effect when
affected or inhibited. Proteases and glucosidases constitute the earliest discoveries of such host
factors, whereas other candidates (kinases, cholesterol synthesis enzymes, proteins involved in
immune response,…) are progressively discovered and validated through siRNA studies (see below).
Cellular proteases
They are mainly of the furin and signal peptidase type. Furin is involved in the maturation of the M
protein from its precursor prM encoded in the dengue polyprotein. The consensus sequence cleaved by
furin is well defined and could theoretically serve to design inhibitors. However, the delicate
specificity balance between host cell targets of furin and dengue prM has not been fully investigated,
and it is not known at this stage if it would be achievable without side effects. The second candidates
are the signal peptidases, located in the ER membranes, which initiate further dengue polyprotein
processing before NS2b/NS3 protease takes over and maturates the whole NS enzymes. As in the case
of furin, the specificity and balance of effect has not been fully evaluated.
Glucosidases
Several DENV proteins (prM, E, and NS1) are decorated by glycosylation upon travelling through the
ER. They are however further maturated upon de-glycosylation by cellular glucosidases I and II,
18
which leaves a single carbohydrate unit at their surface. It has been shown that inhibition of these
enzymes has a potent antiviral effect, since these maturation events are required for proper folding of
the viral proteins. Glucosidases have a very long record of study regarding their inhibition, and many
carbohydrates and carbohydrate mimics have been synthesized and shown to be potent glucosidase
inhibitors in vitro and in vivo. Castanospermin and deoxynojirimycin derivatives have been evaluated
against dengue (and other viruses) and shown interesting antiviral effects. Castanospermin seems
specific for dengue when assayed on West Nile and Yellow Fever viruses. Interestingly, the compound
is safe in mice and protects them efficiently against lethal DENV challenge, indicating that this
research avenue is worth further effort.
Other recent targets
A screen of 120 kinase inhibitors resulted in the discovery of the anti-dengue effect of dasatinib, a
known c-Src kinase inhibitor. Phosphorylation of proteins by kinases is involved in many signal
transduction and regulation pathways such as endocytosis, cell survival and immune evasion during
viral infection. It thus represents a potential avenue to design potent anti-dengue drugs since the kinase
inhibitor field is very active and has produced a very large number of original compounds. Another
recent point-of-action for the dengue drug designer is the cholesterol metabolism, since membrane
cholesterol is involved in DENV (and other flavis) entry and replication. The specific targetting of
cholesterol synthesizing enzymes through siRNA has shown that this avenue is promising, and again,
since cholesterol metabolism is an active area in drug design, crossover drugs may unexpectedly
appear as the dengue problem reaches the interest of mainstream pharmaceutical companies.
There are a large number of viral-cellular protein interactions that have to be discovered and that will
constitute targets to either control viral growth or pathogenicity, or both. A significant dengue-cellular
protein interactome is not known yet, but few discoveries in this direction have already provided
potentially interesting interesting avenues. For example, the binding of STAT2 to DENV NS5 and the
resulting dampening of the interferon response illustrates a direct interaction at work, whereas the
impact of importin a and b binding to the NS5 polymerase has not been fully evaluated yet. Many
protein-protein interactions are to be discovered and will provide novel drug design subjects, alone or
in conjunction with other targets.
siRNAs as tools and/or therapeutic agents
Recently, genome-wide studies have allowed a complete re-assessment of host factors involved in
dengue infection. The use of large-scale siRNA screens has generated large list (>100 proteins) of host
factors involved in helping DENV to achieve its replication cycle. These host factors are potential
targets for drug design taking into accounts the caveats mentioned above. It is interesting to note that
very few of the previously known host factors (proteases, glucosidases, etc…) have been found with
these siRNA screens, indicating that a better resolutive power of these techniques is expected to yield
19
additional targets. Also, these pioneering studies aim at monogenic effects, and future screens will
certainly address more precisely the identification of several genes acting inside a pathway requested
for DENV growth. In addition, these screens did not (in fact, could not) identify innate immunity
genes that defend the cell against DENV infection. The way these defenders are induced and regulated
will certainly provide interesting avenues of research in the future.
Are siRNA interesting as therapeutic agents per se? siRNA have largely proven their efficacy in vitro,
but there are several hurdles that have to be overcome before they become drugs. The most important
issue is the delivery of siRNA in patients. Since tissue tropism is a key issue in viral infections, the
only almost certain use of siRNAs is for delivery in the skin or in the liver, which for dengue disease,
is not sufficient yet. siRNAs will be either delivered (synthetic modified siRNAs of increased
stability) or made available through in vivo expression, the latter being far from reaching anti-dengue
clinical application.
Response modifiers
As any pathogenic virus, DENV infection provokes a large number of distincts and intertwined
responses in the host cell, tissues, and whole organism. Whilst it is probably not necessary to engage
into a therapeutic action against a mere fever, there has been considerable interest in monitoring signs
that would predict the potential evolution of the patient towards severe disease forms. Indeed, after
initial fever and detectable viremia, there is a partial remission generally followed by severe effects
that can lead to fatalities though hemorrhagic fever and shock syndrome. Therefore, any treatment that
would dampen or control this dangerous secondary response without jeopardizing the host antiviral
response would certainly find its place in the therapeutic arsenal.
The most common observation around hemorrhagic fever and vascular leakage, are
thrombocytopoenia, neutropoenia, elevated liver enzymes, elevated serum cytokine levels and
disseminated intravascular coagulation. Hemorrhagic fever can progress to a life-threatening shock
syndrome, a hypotensive state with unrecordable pulse and blood pressure.
A lot of current research is ongoing on the pathogenesis. The pathogenic effects of this secondary
response are believed to be due to a “cytokine tsunami” involving T cells types: Th1 switching to Th2,
TS, Th3, Tr1, memory T, and TCF, on top of which B cell response and antibody dependent
enhancement may synergize the adverse effects.
During the last decades, nitric oxyde induction has been pointed as been associated to many virus
infections. NO level changes have been observed upon dengue infection of cells, mice, and patients.
The role of NO has been investigated, but its pleiotropic role in general metabolism, immune system,
and inflammation, precludes a clear answer regarding its involvement in pathogenesis. Precise control
of NO synthase(s) remains to be experimentally achieved to decipher the precise NO role according to
patient (eg., previous infection), virus serotype, and other parameters. It may then well be that these
data would serve to adjust the host response to desired levels. NO has be reported to directly inhibit
20
the DENV RNA-dependent RNA polymerase, and a potential site of action has been mapped onto NS5
which could explain the different sequence-dependent NO sensivities observed. Again, this
preliminary data deserves a closer look on larger samples of patients and viruses.
Monoclonal antibodies
Many different monoclonal antibodies have been raised against dengue proteins. Although it seems
that the cost associated with both production and use remain prohibitive, only the future will tell if this
therapeutic avenue becomes available cost-effectively in clinical settings.
From the scientific and medical point-of-view, the first most important problem is to address the
Antibody Dependent Enhancement (ADE) of infection problem upon use of an antibody. This problem
is common to Mab and vaccine design. Several antibodies have been described, and in most cases,
their therapeutic potential has been examined in the context of the ADE problem. Not surprisingly, all
of them are directed against the envelope protein. Antibody engineering to prevent FcγR binding
shows potential to design safe and potent therapeutic antibodies. Several pharmaceutical companies
involved in this research avenue are listed below.
Mechanical devices
Mechanical devices have been proposed to assist in the treatment of drug- and vaccine-resistant
pathogens. These devices are to be used during the viremic phase during which circulating viruses are
trapped by the device fed by the blood stream. Purified blood is produced and re-delivered to the
patient, and the treatment is sought to provide first line countermeasure in the absence of drug or
vaccine treatments. The technology converges the blood filtration principles established in
hemodialysis and plasmapheresis with the immobilization of affinity agents (eg., lectins) that capture
enveloped viruses by the surface carbohydrate structures they have evolved to evade the natural
immune response. The device increases the likelihood that a patient's own immune response can
overcome infection (see patent list 2009). It is not yet known if such devices can effectively achieve a
sufficient drop of virus titer to prevent severe dengue.
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Part 3. Academic and academy-associated research centers
Support of dengue antiviral research
With the increasing awareness of dengue emergence and spread around the world, support for dengue
research has been growing, too. Many countries have government agencies funding dengue research in
specific or general programs. The most active (ie., having a significant number of projects funded in
the last 10 years) and large-scale funding agencies are the National Institute of Health (USA), the
European Research Area (EU, Framework programs 4-7), and the Wellcome Trust (UK).
• National Institute of Health (NIH, through its own National Institute of Allergy and Infec-
tious Diseases (NIAID), is currently supporting many projects on dengue antiviral develop-
ment. Several efforts are currently ongoing to develop drugs that target viral and cellular pro-
teins required for dengue replication and therapeutic monoclonal antibodies. NIAID is also
supporting the screening of compounds for efficacy in vitro against dengue. Several thousand
compounds have been screened since 2004 and approximately 50 of them have been identified
for further evaluation. In addition, NIAID is supporting the development of new murine mo-
dels for dengue. These models will be used to evaluate the in vivo efficacy of promising com-
pounds submitted by the scientific community. A list of projects currently funded by NIH on
dengue and other diseases can be found at: projectreporter.nih.gov/
• European Research Area, The European commission has been supporting research programs
on infectious diseases and other since 199’ in its 4th framework program (FP), up to its its 7 th
ongoing FP. A total of 25 projects on dengue have been supported, which can be found at the
following url: http://cordis.europa.eu/search/index.cfm?
fuseaction=search.resultlist&#q=27AB3D69F84955931621A4395513A8D9@showtype=proj
@page=1@perPage=10@sortBy=RELEVANCE@sortOrder=DESC
The most recent large-scale funding on dengue antiviral drug discovery and design is from the
FP7-SILVER project, which has dengue as one out of its three main targets for antivirals.
• The Wellcome Trust, The Wellcome trust has been supporting many projects on dengue over
the past 10 years (see http://www.wellcome.ac.uk/). In 2009, this institution has funded prob-
ably the most important funded dengue research project entirely dedicated to drug design
(http://www.wellcome.ac.uk/News/2009/News/WTX057192.htm) with a total of 2.6 million €
for the whole project.
•
22
• The International Consortium on Anti-virals (ICAV), The International Consortium on An-
ti-Virals (ICAV, see www.icav-citav.ca) is a not-for-profit drug development organization ded-
icated to the discovery and development of antiviral therapies for neglected and emerging dis-
eases. ICAV operates through the establishment of network of collaborative labs on defined
viruses and viral targets. ICAV raises awareness of governements, funding agencies and di-
verse stakeholders about possible pandemies and emerging virus threats. Dengue has been and
is on their priority list. ICAV has a potential of rapid mobilization of a defined lab network to-
wards solving a problem related to the development of any antiviral (eg., hit discovery, ADME
tox studies, etc…). One long term goal of ICAV is global access to affordable anti-viral ther-
apies.
23
Academic and Academy associated research centers
• Center for Infectious Disease Research, University of Queensland, Australia
(http://www.cidr.uq.edu.au) The CIDR has long been involved in dengue research and more
specifically into antiviral drug target characterization, drug discovery and design, with at least
5 of it research groups having dengue and flaviviruses as a major area of study. Small
molecule library screening has identified E protein ligands with anti-flavivirus properties.
Specific research teams: Alexander Khromykh, RNA Virology Laboratory, Dr. Paul Young,
and and Roy Hall, Molecular and Virology Unit
http://www.cidr.uq.edu.au/?page_id=46
http://www.cidr.uq.edu.au/?page_id=76
http://www..cidr.uq.edu.au/?page_id=122
• Drexell University, PA, USA (http://www.drexel.edu) Drexell University (Drexel Institute for
Biotechnology and Virology Research), in association with PharmBridge, has drawn on the
known effect of cellular glucosidase inhibitors, and synthesized novel series of compounds
around the iminosugar pharmacophore. Pharmabridge Inc. (Pensylvania) has no dedicated
Dengue research per se but provides contract research and development activities for
pharmaceutical, biotechnology and agricultural industries. Drexel teams have recently
reported the broad spectrum anti-dengue activity of alkylated porphyrins, geneticin, as well as
that of alpha glucosidase inhibitors in combination with ribavirin. Specific research team:
Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research,
Dr. Jinhong Chang, http://www.drexelmed.edu/Home/AboutOurFaculty/JinhongChang.aspx
• DUKE-NUS Graduate Medical School, (http://www.duke-nus.edu.sg ) Program in Emerging
Infectious Diseases, Singapore, has been performing genome-wide analysis to identify host
factors involved in dengue infection as well as investigating monoclonal antibodies NS3
potentially interesting in therapy. Specific research teams are hosted in the department of
Emerging Infectious Diseases, whose program director is Dr. Gubler, Duane J.,
http://www.duke-nus.edu.sg/web/research_signature_research_programs_emerging.htm
• Florida Gulf Coast University, Department of Biological Sciences, Fort Myers, Florida,
USA, (http://www.fgcu.edu/cas/Departments/biosci.html) has identified p-sulfoxy cinnamic
acid as an entry inhibitor, and also patented peptides targeting the entry process of dengue
24
virus. Specific research team: Biotechnology Research Group, Drs. Scott F. Michael, Sharon
Isern, and Joshua M. Costin , http://www.fgcu.edu/CAS/Biotechnology/ALC.html
• Fundación Instituto Leloir, Buenos Aires, Argentina, (http://www.leloir.org.ar) has
characterized promotor and cyclization elements of the dengue RNA genome that bear
potential as original antiviral targets. Specific research team: Molecular Virology Laboratory,
Dr. Andrea Gamarnik
http://www.friendsofleloir.org/research/molecularvir.htm
http://www.hhmi.org/research/international/gamarnik_bio.html
• The Harvard Medical School, Department of Biological Chemistry and Molecular
Pharmacology, Boston, Massachusetts, USA, (http://bcmp.med.harvard.edu/) has produced
pioneering information on the E protein structure and mechanism, identified a pocket suitable
for ligand binding, and followed peptide design to inhibit the dengue virus entry/fusion
process. Specific research team: Laboratory of Structural Cell Biology, Dr. Stephen C.
Harrison
http://crystal.harvard.edu
https://bcmp.med.harvard.edu/faculty/harrison
• Institut Pasteur -Hong Kong (http://www.hkupasteur.hku.hk) has developed and patented a
cell-based system to produce virus-like particles for the four serotypes of the dengue virus by
co-expressing the two prM and E viral structural proteins in host cells. Applications are
foreseen in serodiagnosis, monoclonal antibody development, drug screening and vaccine
development. Specific research team: Virus-Host Interactions, Dr. Béatrice Nal
http://www.hkupasteur.hku.hk/index.php/research/virus_cell_biology
• Institute for Antiviral Research, Utah State university, Logan, USA
(http://www.usu.edu/iar/iar_home.html)The Institute for Antiviral Research of Utah State
University performs research oriented toward the control of viral diseases. Researchers of the
Institute perform fee-for-service evaluations for corporate industry. Evaluation of 2’-C methyl
nucleoside, initially intended for HCV, has been evaluated for dengue. Specific research
team: Dr. Justin Julander, http://www.usu.edu/iar/Faculty/justin/justin_home.html
• Instituto di Ricerca in Biomedicina, (http://www.irb.ch), Bellizona, Switzerland is
investigating antibodies and their therapeutic potential against dengue, studied amongst other
25
viruses. Developments on dengue are collaborative with HuMabs, a biotech company
belonging to a company consortium operated by Synergenics LLC
http://www.synergenics.net. Specific research teams: Cellular immunology,
Dr. Federica Sallusto,
http://www.irb.ch/index.php?
option=com_jresearch&view=researcharea&task=show&id=3&Itemid=86,
Immune regulation, Dr. Andrea Lanzavecchia,
http://www.irb.ch/index.php?
option=com_jresearch&view=researcharea&id=2&task=show&Itemid=112
• John Paul II Catholic University of Lublin, Department of Molecular Biology, Lublin,
Poland (http://www.kul.pl), has synthesized inhibitors of the Flaviviridae helicases, peptide-
like and small molecules. A collaboration is active with the Laboratory for Drug Design and
Synthesis, University of Maryland, Baltimore, Maryland, USA. Specific research team:
Department of Molecular Biology, Dr. Borowski Peter,
• Mahidol University, Laboratory of Molecular Virology, Institute of Molecular Biosciences,
Nakornpathom, Thailand, (http://www.mb.mahidol.ac.th/mben) has been conduction structure-
base drug design against the protease NS2b/NS3. The National Center for Genetic
Engineering and Biotechnology (BIOTEC), National Science and Technology Development,
Mahidol University (www.biotec.or.th/biotechnology-en/en/index.asp) has discovered
Viprolaxikine, a small cytokine-like protein with strong anti-dengue effects in dengue virus
infected cells. Specific research team: Virology Research Group, Dr. Duncan R. Smith
http://www.mb.mahidol.ac.th/mben/index.php/research/research-group/virology
• Memorial Sloan-Kettering Cancer Center, HTS Core Facility, Molecular Pharmacology
and Chemistry Program, New York, USA (http://www.mskcc.org/mskcc/html/52147.cfm).
The center has established screening facilities and know-how, and recently reported the
screening of 5,632 well-characterized bioactives, yielding 73 confirmed compounds with
IC₅₀ potencies ranging from 60 nM to 9 μM and yielding a hit rate of 1.3%. Specific
research team: HTS Core Facility, Molecular Pharmacology and Chemistry Program, Dr.
Hakim Djaballah
http://www.mskcc.org/mskcc/html/52402.cfm
http://www.mskcc.org/mskcc/html/5785.cfm
26
• Nanyang Technological University, School of Biological Sciences, Singapore,
(http://www.sbs.ntu.edu.sg/Pages/Home.aspx) has played a pivotal role in characterizing
dengue protein structures useful for drug design in collaboration with University of Marseille
and Novartis-NITD, and follows a close collaboration with Novartis-NITD in many aspects of
anti-dengue drug design. Specific research team: School of Biological Sciences, Dr. Julien
Lescar, http://www.sbs.ntu.edu.sg/AboutSBS/Faculty/Julien/Pages/Home.aspx
• National Chemical Laboratory (http://www.ncl-india.org/)and National Institute of
Virology (http://www.niv.co.in/) Pune, India, are developing together anti-dengue drugs from
Indian natural products using innovative and semi-automated fractionation procedures.
Specific research teams : Dengue Group, Drs. Dayaraj C. & Dr. P.S. Shah,
http://www.niv.co.in/annual_reports/Annual_Report_08-09/4%20chp%20Dengue
%20group.pdf
• Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh
City, Viet Nam. (http://www.tropicalmedicine.ox.ac.uk/viet-nam) This institution has been and
is conducting clinical trial of anti-dengue compounds, chloroquine and nucleoside analogue
(see Roche), respectively. It is currently the first and only center known in the world to
perform clinical trials on dengue drugs. Specific research team :
Dr. Cameron P. Simmons, http://www.tropicalmedicine.ox.ac.uk/cameron-simmons-2
Dr. Jeremy Farrar, http://www.tropicalmedicine.ox.ac.uk/jeremy-farrar
• Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology,
School of Pharmacy and Pharmaceutical Sciences and the Purdue Cancer Center, West
Lafayette, Indiana, USA, (http://www.mcmp.purdue.edu/) in addition to its pioneering work
on dengue structural proteins, has performed virtual screening of compounds on the E protein
and identified thiazole compounds active in dengue infected cells. Specific research team :
Department of Medicinal Chemistry and Molecular Pharmacology, Dr. Carol B. Post
http://www.mcmp.purdue.edu/faculty/?uid=cbp
Department of Biological Sciences, Dr. Richard J. Kuhn,
http://www.bio.purdue.edu/people/faculty/index.php?refID=16
Department of Biological Sciences, Dr. Michael. G. Rossmann,
http://www.bio.purdue.edu/people/faculty/index.php?refID=81
27
• Rega Institute Katholieke Universiteit Leuven (http://www.kuleuven.be/rega/rei/). The
Laboratory for virology and Experimental Chemotherapy has a long record of anti-dengue and
anti-flavirus compound isolation and characterization from very diverse sources, using dengue
virus infected cells. This lab and the "Centre for Drug Design and Discovery" (CD3) at
K.U.Leuven have received in 2009 a total of 2.8 million euro from the British Wellcome Trust.
They will apply these funds to the search for possible new medication for the treatment of
infections related to the dengue virus. The virology lab has and is also involved in large scale
EU projects targeting dengue (VIZIER-FP6, SILVER FP7 projects, respectively). Specific
research team : Laboratory of Virology and Chemotherapy, Dr. Johan Neyts,
http://www.kuleuven.be/rega/cmt/JN/group%20JN.html
• Shanghai Institute of Materia Medica, Shanghai, China (http://english.simm.cas.cn), The
Shanghai Institute of Materia Medica has reported that WSS45, a sulfated alpha-D-glucan
isolated from the medicinal plant Gastrodia elata, strongly interferes with Dengue 2 virus
infection in vitro, probably through the inhibition of virus binding to the host cell.Specific
research team : Laboratory of Immunopharmacology and Shanghai Institute of Materia
Medica, Dr. Zuo J.P.
• Southern Research Institute, Birmingham, AL, USA (http://www.southernresearch.org)
The Southern research Institute is a diversified network of collaborative centers for scientific
discovery and technology development. Their current capabilities implementation includes In
vitro services for studies related to dengue and West Nile viruses, amongst others.Specific
research team : Infectious Disease Program, Dr. James W. Noah,
http://www.southernresearch.org/life-sciences/biochemistry-molecular-biology/infectious-
disease-program
• State Key Laboratory of Virology, Wuhan Institute of Virology, China
(http://english.whiov.cas.cn/rh/rd/200907/t20090724_25180.html). The institute has identified
palmatin as a compound targeting the NS2b/NS3 protease, and has worked in collaboration
with the Wadsworth Center in the discovery and evaluation of anti-dengue compounds (see
Wadsworth Center). Specific research team : Dr. Zhiming Yuan
• Universidad de Buenos Aires, Departamento de Química Orgánica, Buenos Aires,
Argentina (http://www.qo.fcen.uba.ar) has a long record of isolation anti-dengue molecules
28
from natural sources, as well as synthesis/hemi-synthesis of antivirals against dengue and
other hemorrhagic fever viruses. Specific research team: Dr. Elsa Damonte
• Université de la Mediterannée – Aix Marseille II - Centre National de la Recherche
Scientifique, Marseille, France (http://www.afmb.univ-mrs.fr) has a record of studies on
dengue replication and capping enzymes and their use in drug design. The virology
department is operating a screening platform with dengue as a top project including enzyme-,
and replicon-based assays, with a collaborative hit validation on dengue virus infected cells.
The virology department is involved in the EU-FP7 SILVER project having dengue drug
design as a major focus. Specific research team: Dr. Bruno Canard, http://www.afmb.univ-
mrs.fr/-Replicases-Virales-Structure-
• University of Berkeley, (http://sph.berkeley.edu/index.php). The Harris Laboratory, Division
of Infectious Diseases and Vaccinology, School of Public Health, University of California,
Berkeley (http://sph.berkeley.edu/faculty/harris.php) has a long-standing interest and track
record in many aspects of dengue research connected to antiviral research, such as the
evaluation of mycophenolic acid, interferons, and therapeutic monoclonal antibodies, and
definition of RNA elements in the 5' and 3' untranslated regions that are critical for translation
and replication. The Harris laboratory has established a mouse model of dengue pathogenesis
and antibody-dependent enhancement (ADE) of disease to study the potential for various
therapeutic candidates that 1) target the virus or host processes necessary for the viral life-
cycle, 2) interfere with the virus-antibody-Fc receptor interaction thereby inhibiting ADE, or
3) reduce dengue disease mediated by inflammation/vascular leakage. More recently, a
partnership with Nanoviricides Inc. has been set up to evaluate drugs in dengue virus-infected
cells and the mouse model of disease, the latter constituting a strong and active field of
research. Specific research team: Dr. Eva Harris, http://sph.berkeley.edu/faculty/harris.php
• University of Bristol, School of Medical Sciences (http://www.bris.ac.uk/fmvs/), has
developped replicons and infectious clones useful for mutation evaluation and drug sensitivity
studies. Specific research team : Department of Cellular and Molecular Medicine, Dr.
Andrew Davidson, http://www.bris.ac.uk/cellmolmed/staff/davidson.html
• University of Malaya, Department of Molecular Medicine, Faculty of Medicine, Malaysia
(http://umfacts.um.edu.my) has discovered and evaluated antiviral actions of flavanoid-
derived compounds on dengue virus type-2. Specific research team : Department of
29
Molecular Medicine, Dr. Rohana Binti Yusof, http://umexpert.um.edu.my/papar_cv.php?
id=AAAJxnAAQAAAF9nAAO
• University of Texas Medical Branch, Department of Biochemistry and Molecular Biology,
Galveston, TX, USA, (http://www.utmb.edu/) The University of Texas Medical Branch,
Department of Biochemistry and Molecular Biology has launched the program "discovering
dengue drugs together" (http://www.utmb.edu/discoveringdenguedrugs-together/) and has
focused so far on antiviral discovery and design targeting the dengue protease. Specific
research team : Dr. Stanley J Watowich http://www.utmb.edu/scvd/staff.asp?ID=45
• Wadsworth Center, New York State Department of Health, and Department of Biomedical
Sciences, University at Albany, State University of New York, Albany, New York, USA
(http://www.wadsworth.org). The center and laboratory has been characterizing dengue
replicons, proteins and enzymes as targets for anti-dengue therapy, as well as discovering and
evaluating compounds, such as Brequinar, triaryl pyroazoline, PMO compounds (in
collaboration with Avi Biopharma), cyclosporin, a series of adenosine analogues related to
NITD008. Specific research team : Dr. Pei-Yong Shi. & Hongmin Li.
http://www.wadsworth.org/bms/index.html
• Washington University School of Medicine, Department of Medicine, St. Louis, USA,
(http://medschool.wustl.edu) has a long record in studies of dengue antibodies having
therapeutic potential. Specific research team : Diamond Lab Research, Department of
Molecular Microbiology, http://microbiology.wustl.edu/Research/diamondRES.html
30
Part 4. The current industrial network of AV discovery
The first observation is that major pharmaceutical companies have not openly entered the field of
antivirals against dengue. No such company has any drug neither on their available product, nor on
their accessible list of products under development. However, some of these companies are developing
anti-dengue drugs, under two circumstances: either anti-dengue drugs were initially intended anti-
HCV drugs, or they are undertaking exploratory research and dengue field surveillance without
significant advertisement.
Pharmaceutical companies and R&D centers involved in dengue therapeutics
• Alios BioPharma (http://www.aliosbiopharma.com/) Alios BioPharma is developing novel
medicines to treat diseases in virology by activating pathways in the innate immune system.
Alios is pursuing the development of small-molecule and protein therapeutics. Small
molecules are of two general kinds: phosphate-protected nucleotides to ensure best
bioavailability through improved membrane crossing, and small RNaseL activators. The
company also develops modified interferons of improved properties, and although not directly,
dengue therapeutics is significantly addressed by Alios BioPharma activities and products.
• Alnylam Pharmaceuticals (http://w.alnylam.com) Alnylam is involved in the development of
RNAi-based innovative approaches targeting many different diseases. Although dengue is not
specifically mentionned, one of their focus is to obtain broad spectrum RNAi anti-viral
therapeutics against hemorrhagic fever viruses through collaborative biodefence programs.
• Apath (http://www.apath.com/) Apath is mainly a technology licensing company with a focus
on hepatitis C virus (HCV) and other medically important RNA viruses including, influenza
virus, respiratory syncytial virus (RSV), and hemorrhagic fever viruses. Apath contacts and
follows clients in the discovery and development of novel therapeutic products for the
treatment of viral infections, amongst which Dengue, West Nile and Yellow fever viruses are
mentioned. Apath has a proprietary antiviral screening platform, and all replicon technologies
useful for drug discovery studies.
• Arrow Therapeutics (http://www.astrazeneca.co.uk/) Arrow Therapeutics, Ltd., a
pharmaceutical company, focuses on the discovery and development of antiviral therapies. It
specializes in small molecule drugs with novel mechanisms of action, for respiratory syncytial
and hepatitis C virus, and has expressed interest and commitment in dengue antiviral research.
31
• Avi BioPharma (http://www.avibio.com/) Avi BioPharma is developping modified
oligonucleotides of the phosphorodiamidate morpholino oligomers, conjugated or not to
peptides. These chemicals target RNA structures with great specificity, since some of their
best compounds are devoid of activity on West-Nile virus. The main focus of the company in
antiviral research is Influenza and Dengue.
• Biota (http://www.biota.com.au) Biota is an antiviral drug discovery and development
company focusing mainly on viral respiratory diseases (RSV, Rhinoviruses, and Influenza).
Although not directly involved in dengue antiviral research, Biota has discovered and is
developing a novel class of antiviral nucleoside drugs which inhibit the HCV polymerase.
• Biotron (http://www.biotron.com.au/) Biotron is focusing on "viroporins”, which are ion
channels involved in the ion traffic across membranes. Since virus replication is tighly
associated with membranes, small molecules blocking the ion channel activity of viroporins
are able to inhibit viral budding and replication. In the case of Dengue, the company is
focusing on the M protein.
• Botanic century (http://www.botaniccentury.com/index.asp) Botanic century and Phynova are
associated to investigate a plant extract (PYN-18) that has shown potent anti-dengue (as well
as anti-HCV) activity. PYN18 does not target viral absorption, replication, formation or
secretion of progeny virus. PYN18 appears to interfere with viral maturation such that
progeny virus is not infective to host cells.
• Canopus BioPharma (http://www.canopusbiopharma.com/) Canopus Biopharma is
developping CB5300 as a lead compound against Dengue. CB5300 is a product identified
long ago, used in the food industry since 1813, and generally recognized as safe (GRAS). It
was initially developped by Canopus BioPharma against HCV, and is thus a by product raising
interest in the field of antivirals against dengue. Although no information is available yet on
the nature of the product, it is expected to have a cellular target and systemic effect conferring
anti-dengue properties.
• Chimerix (http://www.chimerix-inc.com) Chimerix is an antiviral company screening
compounds to address several clinically significant viruses. Dengue virus is listed in their
currently active research program.
32
• Center for Genetic Engineering and Biotechnology, CIGB (http://www.cigb.edu.cu/)
Although most of the efforts of the CIGB are oriented towards vaccine research, the CIGB is
developping antiviral molecules targeting dengue endocytic receptors, as well as peptides
targeting the NS3/NS2b protease. The CIGB is the first and only example of an institution
having a corporate activity (mixed with academic research) on dengue and other viral diseases
in low income countries.
• Functional Genetics (http://www.functional-genetics.com/) Functional Genetics is
developing antivirals (monoclonal antibodis and small molecules) that can treat or prevent a
broad spectrum of different viral diseases. Although not mentionned directly, dengue may
become a target of this company addressing mainly host cell targets.
• Genelabs technologies (http://www.genelabs.com) Genelabs technologies is an antiviral drug
discovery and design company focusing on HCV, and having advanced HCV nucleoside
inhibitors targeting the NS5b polymerase. Although not specifically mentionned, these
inhibitors may prove interesing for dengue. Genelabs has collaborated with Novartis and
Gilead in several scientific programs.
• Genodysse (http://www.genodyssee.com/), Genodyssee is a drug discovery company
specialized in the identification of host cell factors involved in response to diseases, and in
particular, viral infections. The company has isolated highly efficient interferons that will
probably raise interest beyond the initial intented use for HCV infections.
• International Center for Genetic Engineering and Biotechnology (ICGEB)
(http://www.icgeb.org/home.html) Beside their important reserach activity on Dengue vaccine
and diagnostics, the ICGEB has patented the use of activity Cissampelos pariera extracts
against Dengue, in a joint collaboration and application with Ranbaxy Research Laboratory,
now Daiichi Sankyo India Pharma Private Limited.
• Idenix Pharmaceuticals (http://www.idenix.com/) Idenix has no research and products
against dengue per se, but HCV compounds may find an additional or second life in dengue
antiviral research. This is particularly true for nucleoside analogues inhibitors of the HCV
NS5b RNA polymerase, which are very likely to inhibit the related dengue virus NS5 RNA
polymerase. In september 2010, the FDA had verbally informed Idenix that it should halt
study of two of those HCV compounds (IDX184 (completed Phase IIa) and IDX320
(completed Phase I)) due to three adverse events that had cropped up during a combination
33
study of the two drugs. In the case of dengue, the short duration of the treatment may
accommodate these adverse effects, even more if the drugs do not show adverse effects when
give alone. In any case, re-evaluation of Idenix nucleoside analogue library may well uncover
interesting anti-dengue molecules. Novartis has 47% share in Idenix.
• Kineta (http://www.kinetabio.com/) Kineta is developing drug candidates that activate RIG-I,
a natural disease-fighting mechanism within the immune system. Research is focused on the
development of broad based antiviral products targeting, amongst others, hepatitic C and West
Nile viruses. Kineta has a proprietary screening platform
• Macrogenics (http://ww.macrogenics.com) Macrogenics discovers, develops and
commercializes antibody-based therapeutics spanning multiple therapeutic areas, including
immunology, oncology, respiratory, cardiometabolic and infectious diseases. A West Nile Mab
is under clinical phase II. For dengue, Macrogenics is developing an antibody for post-
exposure prophylaxis through funding by NIH.
• Nanoviricides (http://www.nanoviricides.com) The aim of Nanoviricides is to discover
compounds acting like microbicides, i.e., attacking enveloped virus particles and dismantling
them. Nanoviricides has established collaboration with USAMRIID to work on a large panel
of pathogenic human viruses, including dengue and flaviviruses. They have Identified drug
candidates showing efficacy in animals. In collaboration with Dr. E. Harris (University of
California, Berkeley), data has been obtained showing increased survival and decreased viral
load in a dengue virus-infected mouse model.
• Novartis and Novartis Institute of Tropical Diseases (http://www.novartis.com) Novartis is
one of the world largest drug discovery and design company. Novartis interest in Dengue is
carried mainly through the Novartis Institute of Tropical Diseases (NITD), which is mainly a
small-molecule drug discovery research institute dedicated to new treatments and prevention
methods for dengue, tuberculosis and malaria, and potentially by Idenix (into which Novartis
has ~45 % share). The goal of NITD is to make treatments readily available, without profit, to
patients of developing countries. NITD is by far the most active private institution. NITD has
published the greatest number (>50 in december 2010) of scientific publications and patents in
the dengue antiviral field since 2005. NITD is also the earliest institute having explicitly and
publicly put dengue as a priority. Initial efforts of NITD have focused on the dengue
NS2b/NS3 protease. NITD has conducted a large-scale HTS (1.4 million compounds and
identified interesting hits, but so far none has entered the development pipeline yet. For an
34
unknown number of research teams, the impact on NS2b/NS3 inhibitor discovery of the
fabricated and erroneous crystal structure of dengue NS3 protease domain (published in
1999) remains to be evaluated. NITD has followed as many targets as possible from the virus
and also from the host, with significant impact in the field. These targets are the envelope
protein E (entry and fusion inhibitors), NS3 protease and helicase, NS4b association with
NS3, NS5 methyltransferase and RNA polymerase (for which 1 million compounds have been
screened), as well as conducted many studies (genome wide-, immunological-, membrane
studies, assays systems,...) that could identify or lead to cellular targets. Monoclonal
antibodies have been described with a potential therapeutic use.
NITD’s most advanced target and corresponding compounds is the NS5 MTase/polymerase.
NITD008 is an adenosine analogue first of a series studies by NITD, showing very interesting
properties, but abandoned because of unfavorable toxicity. A follow-up of this compound was
pursued with NITD449, further bonified with a prodrug approach to yield NITD203.
Unfortunately, the toxicity of the product neither reached an acceptable level. Follow-up of
this compound was pursued with NITD449, further bonified with a prodrug approach to yield
NITD203. The No-Observable-Adverse-Effect (NOAE) level was not overcome yet, though.
• Pharmasset Inc (http://www.pharmasset.com/) Pharmasset is an antiviral drug discovery,
design, and development company focusing mainly on HIV and HCV, but has several
nucleoside analogues (amongst which one is in collaboration with Roche) in clinical trails
against HCV that might eventually prove active against Flaviviridae at large, ie., dengue.
• PharmBridge (http://www.pharmabridgegroup.com/) See Drexel University for project and
compounds. Pharmabridge Inc. provides contract research and development activities for
pharmaceutical, biotechnology and agricultural industries.
• Prosetta Bioconformatics (http://www.prosetta.com) Prosetta Bioconformatics is a
biotechnology company exploring the potential of cell-free protein synthesizing systems for
drug discovery. Major focus is on antiviral research, and dengue targets have been studied (eg.
capsid formation) and followed up to find series of active compounds in dengue infected cells,
in collaboration with USAMRIID
• Replizyme Ltd (http://www.replizyme.com) Replizyme is a service company in the field of
antiviral research, and more specifically on viral polymerases. Both dengue and HCV purified
RNA polymerases are available as reagents and assays, as well as expertise to discover hits
and follow-up the hit-to-lead process.
35
• Retrovirox (http://www.retrovirox.com) RetroVirox is a biotechnology company dedicated to
discovering new treatments for patients with infectious disease. The company focuses on
challenging human pathogens, dengue amongst other viruses. Antiviral assays against Dengue
virus are performed to determine the inhibitory activity of small-molecule compounds and
neutralizing antibodies for vaccine design.
• Roche (http://www.roche.com) Roche has entered very recently the dengue antiviral field with
a drug, Balapiravir, initially designed for HCV infections. It is a cytosine nucleoside analogue
dengue RNA-polymerase inhibitor, which has reached phase IIb against HCV, and been
abandoned because of haematological toxicity. As mentioned previously, the toxicity profile
may be irrelevant in the case of acute dengue infections, and thus, the compound has entered a
clinical trial in march 2010 entitled “Randomized, Double-Blind, Placebo-Controlled Study to
Evaluate the Safety and Efficacy of the Dengue Virus Polymerase Inhibitor (Balapiravir) in
Male Patients With Confirmed Dengue Virus Infection”. The trial is conducted by the Oxford
University Clinical Research Unit in Vietnam, the same institution which has evaluated
chloroquine in a clinical trial.
Likewise, Roche has been working on beta-d-2'-ethynyl-7-deaza-adenosine, a nucleoside
analogue presenting very potent inhibition properties of the Dengue virus RNA polymerase.
Studies were made using the active 5’-triphosphate of the drug in conjunction with purified
polymerases of the four dengue virus serotypes. This drug turned out to be the same as
NITD008, described in a recent paper, and abandoned because of unfavorable toxicity. It does
say, however, that a potential exists for nucleoside analogues targeting this essential dengue
enzyme.
• Sentinext therapeutics (http://www.sentinext.com)
Sentinext therapeutics is developing vaccines and immuno-therapeutics against dengue and
other viral diseases.
• SIGA technologies (http://www.siga.com) SIGA is anti-infectious company focusing mainly
on biodefence-concerning viruses. SIGA uses high-throughput screening technologies to
identify the most likely candidates for therapeutic intervention against, amongst others,
dengue virus. Small molecule inhibitors have been isolated and shown proof-of-concept
efficacy in a murine model.
36
• Spring bank Pharmaceuticals (www.springbankpharm.com) Sping Bank Pharmaceuticals is
following a similar approach as Kineta, using nucleoside analogues turning on the RIG-I
innate immunity defense system against a broad range of viruses.
• Tamir (http://www.tamirbio.com/) Tamir is developing recombinant RNAses targeting cancer
cells as well as virus infected cells. RNA viruses and dengue viruses are amongst their
therapeutic targets. AC 03-636 has entered pre-clinical trials for gliomas and is under
investigation as a potentially broad spectrum antiviral.
• Tibotec (http://www.tibotec.com/) Tibotec is antiviral company, subsidiary of Johnson &
Johnson, known in the anti-HIV and anti-HCV field. Tibotec has shown interest and
commitment in dengue antiviral research.
37
Part 5. Mapping the dengue drug design effort and needs
The location of the research entities described above in Part 3 and 4 are depicted within two
interactive maps at http://denguedrugs.com
The nature and location of academic dengue research centers
Examination of Map1 and Map 2 shows in a striking manner that the vast majority of dengue research
centers is NOT located in dengue-afflicted countries, neither at the academic level (Map 1) nor at the
corporate level (Map 2). The blatant and almost unique exception is NITD in Singapore.
Two continents heavily afflicted by dengue are absent from dengue antiviral research, namely Central
and South america (Latin America), and Africa.
Following the above discussion on natural products and biodiversity, if one considers that the tropical
countries containing the major share of natural molecules bearing anti-dengue potential, we note that
DENV geographical distribution superimposes very well with this natural biodiversity that should
provide drugs in the future.
Strikingly, nearly all low income country located between the tropics has a department of natural
products in its university. This is, in part, due to the natural abundance of plants, the
ethnopharmacological practices, and the impact of the Convention on Biological Diversity (december
1993), establishing access and benefit sharing guidelines. For example, Africa has a well organized
network named Napreca consisting of universities and research organisms dedicated to natural product
research. Napreca (see http://napreca.net/) involves in east and central Africa Bostwana, Cameroon,
Congo, Democratic Republic of Congo, Ethiopia, Kenya, Madagascar, Rwanda, Tanzania, Uganda,
and Zimbabwe.
It is thus obvious that in the future, dengue research will be also conducted in situ as more bottlenecks
(cost, education, technology, policy) are overcome.
Patent activity of the last 6 years (2005-2010)
The list of patents directly relevant to drug design, having dengue as a direct or indirect focus (ie., as a
by product of HCV, or a general antiviral method, …) is reported in Annex 1.
An increase in the number of patent is detectable in the last two years, with a number averaging 20+
patents, whereas this number by about half the years before. Another interesting information is the
nature and content of the patents is evolving.
38
Indeed, one can see in Figure that the proportion of patents having “dengue” or “Flavivirus” (or
“Flaviviridae” when it is specified that it is in addition to HCV) is strongly increasing over the years,
going from 13 % in 2005 to more than 50 % in 2009 and 2009. If this trend continues, on can safely
say that something is happening in the dengue drug design field. Dengue is becoming a major focus,
not a by-product of antiviral research on other clinically and economically important viruses.
Figure 2. The past 6-years patent activity
related antivirals against viruses
amongst which dengue, and patents having
“dengue” or “flavivirus” in their title.
Trends, strengths, and weaknesses of the anti-dengue drug research/development field
The field of dengue drug research has emerged in the past 5 years and is probably here to stay. The
knowledge accumulated both in the drug design field and on DENV specifically allows efficient drugs
to be discovered. It is clear that although perfectible, the scientific and drug design community
possesses tools to synthesize, select, improve, and evaluate drugs in the laboratory. What is the nature
of the bottlenecks, where are they, or more exactly, where have they moved to?
The once often mentioned patient cohort availability for clinical trials has been recently overcome.
The market issue seems to be less significant also, as having private companies investigating the field
is the best and safest indicator of a sizeable market.
On the scientific point-of-view, perhaps the most important bottleneck is that of appropriate animal
model. These are of two kinds, i) a model for infection and protective action of a given drug, ii) a
disease model, that could, as discussed above, also yield interesting therapeutic avenues for tailored
response modifier drugs.
Mice model exist (eg. AG129 mouse), but they have their limitations (eg., low and short viremia).
Taking advantage of the possibility to manipulate mice genetically, other models will have to be
39
developed. Likewise, monkey models exist and would benefit to be optimized regarding which viral
strains (epidemic, sylvatic, clinical, reference, etc…) are they best for.
One last potential limitation to drug development is that dengue disease is perhaps majoritarily a
pediatric disease, and most of the avenues taken in drug design have involved adult patients. This is
not a simple drug-dosage issue. For example, no genome wide research has been conducted comparing
infected infants versus adults. The whole dengue drug research must be at all times evaluated with this
issue in mind, as a potential specific toxicity or adverse effect in children would devastate the still
fragile antiviral drug design field.
Beyond dengue : other relevant viral infections
After having served as an initial model for HCV, dengue research will certainly benefit to research on
other viruses. In fact, dengue provides to the drug designer significant difficulties that may not be
found for other virus infections (eg., pediatric disease, short viremia, disseminated target organs,
encephalitic forms,…). In that respect, all the great effort made for dengue will disseminate to specific
fields, and in first instance, for flaviviruses. In the case of Yellow fever virus, for which there is a very
efficient vaccine, it is not known if the use of a potent antiviral immediately after the onset of
symptoms would save lives from this devastating illness. For encephalitic viruses (JEV, TBE, WNV,
…), the question remains the same regarding neurological symptoms and disease severity.
In the most conserved flavivirus protein (NS5), the amino acid divergence between dengue serotypes 1
- 4 is 20- to- 26% whereas West Nile virus NS5 has only ~33% amino acid divergence with that of
dengue (Table 1)
Table 1. Amino acid conservation between
dengue and West-nile (kunjin isolate) for
the whole ORF (upper part in black) and
NS5 (red and green).
It is thus very likely that drugs targeting conserved flaviviral proteins or generally conserved virus –
host interaction pathways will have a broad activity spectrum amongst flaviviruses. Although this
observation holds for identified BSL-4 viruses, it is important to note that a very significant number of
encephalitis of unknown etiology occur in the tropics. Some are of viral (and flaviviral) origin, and
may give rise to a new emerging flavivirus.
Last, beyond dengue are other viruses that add to the dengue burden. There are no large scale studies
of dengue co-infections with other viral or bacterial/fungal/parasitic pathogenic agents. What about
dengue and HIV? dengue and measles? dengue and malaria? dengue and other seemingly mild
40
pediatric diseases? Etc…We need clearer pictures of these co-infections, as the drug-drug interaction
field is also quite young. This adds complexity to issues related to the patient’s background and its
effect on dengue disease outcome.
How to promote the development of dengue antiviral research?
As shown in the list of pharmaceutical companies, most of the latter are small-size, risk taking
companies investigating research field that are not covered by large pharmaceutical companies. They
are created upon discovery of an active compound which is then patented, or they are investigating
novel avenue of research uncovered by academic discoveries at large (eg., host factors, innate
immunity, etc…). In the former case, they take a “traditional” development scheme, which is
notoriously long, costly, and risky. This may prove even harder in the case of dengue than HCV or
other viruses, and not surprisingly, these companies are not so small… In the latter case (ie.,
innovative novel avenues), they may either subcontract discoveries to larger companies, or grow to a
larger size. There is also a high risk associated to this approach, as business development example do
not abound in these novel fields, and they may anyway meet with a traditional drug design scheme
later on.
Therefore, one can see two ways of favoring the emergence of dengue drug design companies: The
first is a strong academic support to innovative and novel approaches presenting space yet unexplored
by large pharmaceutical companies. This are mainly pathogenesis, genome-wide, host-response, and
innate immunity studies. Significant discoveries will undoubtedly generate new start-ups from
scientists and corporate entrepreneurs. The second incentive is to make chemical molecules available
to whoever has capacity, will, and structure to discover drugs. Natural products are unbeatable in many
aspects described above, and through existing university networks in dengue afflicted countries, they
have the capacity to federate research effort, and foster scientific, medical, and economical
development. As Asia has already made significant efforts in this direction, capacity building remains
to be established in Africa and Latin America.
41
Annex 1. References
Recommended readings
• Dengue (2008) Tropical Medicine: Science and Practice, Vol. 5, Scott B. Halstead Editor,
Imperial College Press.
• Gubler, D., Kuno, G., and Markoff, L. (2007) Flaviviruses, in Fields Virology, Vol.1 Fifth
edition, LWW, Knipe DM and Howley PM, Eds.
• Noble, C. G., Chen, Y. L., Dong, H., Gu, F., Lim, S. P., Schul, W., Wang, Q. Y., Shi, P. Y.
(2010), Stategies for the development of DENV inhibitors, Antiviral Research, 85, 450-462.
Additional references cited in the text :
1. Eggink, D., B. Berkhout, and R. W. Sanders. Inhibition of HIV-1 by Fusion Inhibitors. Curr
Pharm Des 16:3716-28.
2. Elion, G. B., P. A. Furman, J. A. Fyfe, P. de Miranda, L. Beauchamp, and H. J. Schaeffer.
1977. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc
Natl Acad Sci U S A 74:5716-20.
3. Kingston, D. 2011. Modern Natural Products Drug Discovery and IT Relevance to
Biodiversity Conservation. J. Nat. Prod in the press.
4. Newman, D. J., and G. M. Cragg. 2007. Natural products as sources of new drugs over the
last 25 years. J Nat Prod 70:461-77.
5. Pevear, D. C., T. M. Tull, M. E. Seipel, and J. M. Groarke. 1999. Activity of pleconaril
against enteroviruses. Antimicrob Agents Chemother 43:2109-15.
6. Saklani, A., and S. K. Kutty. 2008. Plant-derived compounds in clinical trials. Drug Discov
Today 13:161-71.
7. Stittelaar, K. J., J. Neyts, L. Naesens, G. van Amerongen, R. F. van Lavieren, A. Holy, E.
De Clercq, H. G. Niesters, E. Fries, C. Maas, P. G. Mulder, B. A. van der Zeijst, and A. D.
Osterhaus. 2006. Antiviral treatment is more effective than smallpox vaccination upon lethal
monkeypox virus infection. Nature 439:745-8.
8. Taubenberger, J. K., A. H. Reid, A. E. Krafft, K. E. Bijwaard, and T. G. Fanning. 1997.
Initial genetic characterization of the 1918 "Spanish" influenza virus. Science 275:1793-6.
42
Annex 2. Patents
The search was made with « dengue & antiviral », scientific publications in journals eliminated, and
patents kept and numbered for each year. Sometimes, the patent is applied or obtained in two different
flavors (according to, eg., countries for which it has been granted), but a single mention has been
reported here. Only patents related to dengue antiviral therapy (not diagnostics nor vaccine) are
mentioned. Sometime a method, compound or a target is relevant to dengue as a « side » virus, ie.,
intended at first against another virus.
2010 – 18 patents
1- Preparation of azaindole compounds and methods for antiviral treatment. Maccoss,
Malcolm; Njoroge, F. George; Nomeir, Amin; Chen, Guangming; Karp, Gary Mitchell; Lennox,
William Joseph; Li, Chunshi; Morrill, Christie; Paget, Steven D.; Ren, Hongyu; Zhang, Nanjing;
Zhang, Xiaoyan. (Schering Corporation, USA; PTC Therapeutics, Inc.). PCT Int. Appl. (2010),
228pp. CODEN: PIXXD2 WO 2010117935 A1 20101014 Designated States W: AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK,
DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK,
SL, SM, ST, SV, SY, TH, TJ. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN,
TD, TG. Patent written in English. Application: WO 2010-US29928 20100405. Priority: US
2009-166883 20090406. CAN 153:505795 AN 2010:1277282 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
The invention is directed to compds. of formula I and forms and pharmaceutical compns. thereof
useful for treating a viral infection, or for affecting viral activity by modulating viral replication.
Compds. of formula I wherein W1, W2, W3 and W4 are independently N, CR1 and NO, provided that
one to three of W1 - W4 are N and the remainder are CR1; X is H, halo, CN, NO2, etc.; Y is
(un)substituted aryl, (un)substituted heteroaryl, and (un)substituted heteroaryl-1-oxide; Z is C1-8
alkyl, C2-8 alkenyl-C1-8 alkyl, C2-6 alkynyl-C1-8 alkyl, etc.; R1 is H, halo, OH, CN, NO2, etc.; and
free acids, free bases, salts, hydrates, solvates, clathrates, isotopologues, racemates, enantiomers,
diastereoisomers, stereoisomers and polymorphs thereof, are claimed. Example compd. II was prepd.
43
by a general procedure (procedure given). All the invention compds. were evaluated for their antiviral
activity. From the assay, it was detd. that compd. II exhibited an IC50 value of less than about 0.5 μM.
2- Polynucleotides comprising codon-optimized prME genes from dengue virus types 1-4, their
sequences and use in generation of viral-like particles for drug screening, immunization or
disease treatment. Wang, Peigang; Altmeyer, Ralf Marius; Nal-Rogier, Beatrice Therese Marie;
Kudelko, Mateusz; Despres, Philippe. (Institut Pasteur, Fr.; HKU-Pasteur Research Centre). Can.
Pat. Appl. (2010), 43pp. CODEN: CPXXEB CA 2658259 A1 20100912 Patent written in
English. Application: CA 2009-2658259 20090312. Priority: . CAN 153:424495 AN
2010:1193018 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention provides polynucleotides comprising codon-optimized premembrane glycoprotein M
and E glycoprotein genes (prME) from dengue virus types 1-4 for enhanced expression in mammalian
cells, and their use in generation of virus-like particles (VLPs). The invention also provides for the
use of said VLPs in: (a) eliciting a specific anti-dengue immune response against dengue-assocd.
diseases or infections; (b) screening for agents that inhibit dengue virus prodn.; and (c) treating or
preventing a dengue-assocd. diseases. The invention further provides the sequences of said
polynucleotides that comprise the codon-optimized prME genes. The examples showed that the
optimized DV1 prME gene in transformed HeLa cells enhanced the expression of prME glycoproteins
and thereof facilitated the generation of DV VLPs with native viral proteins
3- Thienopyridine derivatives for the treatment and prevention of dengue virus infections.
Byrd, Chelsea M.; Dai, Dongcheng; Jordan, Robert; Hruby, Dennis E. (Siga Technologies, Inc.,
USA). PCT Int. Appl. (2010), 130pp. CODEN: PIXXD2 WO 2010099166 A1 20100902
Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,
GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU,
LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ. Designated States RW: AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2010-US25183 20100224. Priority: US 2009-156132 20090227. CAN 153:375216 AN
2010:1095820 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
44
Abstract
Methods and pharmaceutical compns. for treating viral infections, by administering certain
thienopyridine deriv. compds. in therapeutically effective amts. are disclosed. Methods of using the
compds. and pharmaceutical compns. thereof are also disclosed. In particular, the treatment and
prophylaxis of viral infections such as caused by flavivirus is disclosed, i.e., including but not limited
to, Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne
encephalitis virus.
4- Antibodies for diagnosis and treatment of flaviviral infections. Vasudevan, Subhash; Lescar,
Julien; Rajamanonmani, Ravikumar. (Nanyang Technological University, Singapore). PCT Int.
Appl. (2010), 107pp. CODEN: PIXXD2 WO 2010093335 A1 20100819 Designated States W:
AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR,
CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI,
FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR, BF, BJ, CF, CG, CI, CM, GA, ML,
MR, NE, SN, TD, TG. Patent written in English. Application: WO 2010-SG49 20100210.
Priority: US 2009-151301 20090210. CAN 153:331827 AN 2010:1039949 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The authors disclose the prepn. of an antibody raised against domain III of dengue virus envelope
glycoprotein (E). The antibody is capable of (1) neutralizing dengue virus; (2) binding to all dengue
serotypes, and (3) cross-reacting with West Nile virus.
5- Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections.
Cho, Jong Hyun; Coats, Steven J.; Schinazi, Raymond F.; Zhang, Hongwang; Zhou, Longhu. (RFS
Pharma, LLC, USA; Emory University). PCT Int. Appl. (2010), 143pp. CODEN: PIXXD2 WO
2010091386 A2 20100812 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG,
BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES,
FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA,
LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL,
NO, PT, SE, SM, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in
45
English. Application: WO 2010-US23563 20100209. Priority: US 2009-150628 20090206. CAN
153:311457 AN 2010:1002272 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Purine nucleoside monophosphates I, wherein R1 is an atom or a group removed in vivo to form OH
when administered as the parent nucleoside, for example halogen, OR, NR2, SR, OCOR, CHCOR,
N(COR)COR, SCOR, OCOOR, NHCOORR is H, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl; W is N, CH, CF, CCN, CC…CH, CC(O)NR2;Y is O,
S; Z is CL2, CL2CL2, CL2OCL2, CL2SCL2, CL2O, OCL2, CL2NHCL2; L is H, F, alkyl, alkenyl,
alkynyl; A is O, S, CH2, CHF, CF2, C=CH2, C=CHF, C=CF2; R2 and R3 are independently OR8; R8
is alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl; R5, R6, R4'-R7' are independently H, halogen, OH,
SH, NH2, NHOH, NHNH2, N3, COOH, CN, COMH2, CSNH2, ester, alkyl, R9, OR9, SR9, SSR9,
NHR9, NR92; R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylaryl, arylalkyl; were prepd. and used
for treating or preventing cancer and viral infections. Thus, nucleotide II was prepd. and tested in
vitro as antitumor and antiviral agent. The title compds. show potent antiviral activity against HIV-1,
HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever, and HBV.
6- Preparation of 1'-substituted carba-nucleoside analogs as antiviral agents carba-nucleoside
analogs for antiviral treatment. Butler, Thomas; Cho, Aesop; Kim, Choung U.; Xu, Jie. (Gilead
Sciences, Inc., USA). U.S. Pat. Appl. Publ. (2010), 91pp. CODEN: USXXCO US 2010203015
A1 20100812 Patent written in English. Application: US 2010-702957 20100209. Priority: US
2009-151248 20090210. CAN 153:287244 AN 2010:1001798 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
Provided are thieno[3,4-d]pyrimidin-7-yl and furo[3,4-d]pyrimidin-7-yl ribosides, riboside phosphates
and prodrugs thereof as well as intermediates and methods of prepn. The compds., compns., and
methods provided are useful for the treatment of Flaviviridae virus infections. 1'-Substituted carba-
nucleoside analogs I, wherein R1-R6 are independently H, OR, NR2, N3, CN, NO2, S(O)nR, halogen,
alkyl, carbocyclyl-alkyl, alkenyl, alkynyl, arylalkyl; any two of R1-R6 on adjacent carbo when taken
together are O(CO)O or when taken together with the ring carbon to which they are attached form a
double bond; n is 0-2; R is H, alkyl, alkenyl, alkynyl, arylalkyl, carbocyclyl-alkyl, acyl, carboxylate
ester, amide, thio ester, sulfonyl, sulfoxide, sulfonamide; R7 is H, acyl, carboxylate ester, amide,
sulfonyl, sulfonamide, substituted phosphorus; R8-R10 are independently halogen, substituted amine,
N3, NO, NO2, CHO, CN, substituted imine, substituted oxime, amide, sulfonamide, carboxylate ester,
x2 is S, O, S(O), SO2; were prepd. and used as antiviral agents. The compds., compns., and methods
provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C
46
infections. Thus, nucleoside II was prepd. and tested as antiviral agent (EC50 10-100 μM), wherein
the viral infection is caused by a virus selected from the group consisting of dengue virus, yellow
fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus,
Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine
viral diarrhea virus, Zika virus and Hepatitis C virus.
7- Anti-dengue activity of Cissampelos pareira extracts. Bhatnagar, Pradip Kumar; Katiyar,
Chandra Kant; Khanna, Navin; Upadhyay, Dilip Jatashankar; Swaminathan, Sathyamangalam;
Srinivas, Kona; Sharma, Navin; Kanaujia, Anil; Sood, Ruchi; Singhal, Smita; Shukla, Gyanesh;
Duggar, Rajeev; Pareek, Pawan Kumar; Singh, Yogendra; Khan, Seema; Raut, Rajendra. (Ranbaxy
Laboratories Limited, India; International Centre for Genetic Engineering and Biotechnology;
Department of Biotechnology). PCT Int. Appl. (2010), 26pp. CODEN: PIXXD2 WO
2010084477 A1 20100729 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG,
BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES,
FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA,
LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL,
NO, PT, SE, SM, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in
English. Application: WO 2010-IB50299 20100123. Priority: IN 2009-DE141 20090123. CAN
153:241902 AN 2010:943245 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention relates to the anti-dengue activity of the Cissampelos pareira exts.
Pharmaceutical compns. comprising exts. of C. pareira and processes for the prepn. of exts. are also
provided. Methanolic ext. of C. pareira showed antiviral activity against all the four serotypes of
dengue (DENV1, DENV2, DENV3 and DENV4) in conventional assay with PRNT50 values in the
range of 1.2-11.1 μg/mL.
8- Targeting and inhibiting replication of dengue virus type I using siRNA. Wu, Xinwei; Wang,
Ming; Du, Lin; Yue, Jinya; Jiang, Liyun. (Guangzhou Disease Prevention and Control Center, Peop.
Rep. China). Faming Zhuanli Shenqing (2010), 11pp. CODEN: CNXXEV CN 101781651 A
20100721 Patent written in Chinese. Application: CN 2009-10036705 20090116. Priority: . CAN
153:306789 AN 2010:926365 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
47
Patent Family Information
Patent No. Kind Date Application No. Date
CN 101781651 A 20100721 CN 2009-10036705 20090116
Priority Application
CN 2009-10036705 20090116
Abstract
This invention relates to a method for targeting and inhibiting the replication of dengue virus type I
using siRNA. The invention provides the sequences of the siRNA mols. used for inhibiting the
replication of dengue virus. The siRNA sequence is screened from those that are designed according
to dengue virus type I genome, and can inhibit dengue virus replication, and prevent cells from being
damaged by dengue virus.
9- Inhibition of viral RNA interaction with host proteins in the inhibition of viral replication in
the treatment of infection. Brinton, Margo A.; Emara, Mohamed M.; Li, Wei. (Georgia State
University Research Foundation, USA). U.S. Pat. Appl. Publ. (2010), 41pp., Cont.-in-part of U.S.
Ser. No. 654,273. CODEN: USXXCO US 2010166704 A1 20100701 Patent written in English.
Application: US 2008-82095 20080407. Priority: US 2002-407105 20020830; US 2003-654273
20030902; US 2007-910611 20070406. CAN 153:135758 AN 2010:820082 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20100166704 A1 20100701 US 2008-82095 20080407
US 20040162252 A1 20040819 US 2003-654273 20030902
Priority Application
US 2002-407105P P 20020830
US 2003-654273 A2 20030902
US 2007-910611P P 20070406
Abstract
Methods of treating viral infection, specifically a flavivirus infection, by blocking the interaction of
viral RNA with host factors to prevent viral replication are described. Specifically, the interaction of
the host TIA-1 and TIAR antigens with the viral RNA 3'-stem-loop structure is identified as a target.
TIAR is shown to be the primary protein binding to the stem-loop structure. Knockout of the host
TIAR gene lowers the efficiency of viral replication in infected cells.
48
10- Non-dividing cell-based assay for high throughput antiviral compound screening. Uprichard,
Susan L.; Yu, Xuemei; Sainz, Bruno, Jr. (University of Illinois, USA). U.S. Pat. Appl. Publ. (2010),
17pp. CODEN: USXXCO US 2010099079 A1 20100422 Patent written in English. Application:
US 2009-566074 20090924. Priority: US 2008-100540 20080926. CAN 152:493425 AN
2010:507665 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20100099079 A1 20100422 US 2009-566074 20090924
Priority Application
US 2008-100540P P 20080926
Abstract
The invention features a cell-based assay that recapitulates all aspects of a viral lifecycle for use in
identifying antiviral agents. The assay employs synchronized, non-dividing host cells and a
fluorescence resonance energy transfer peptide substrate for monitoring endogenous viral protease
activity, which is indicative of viral infection kinetics.
11- Dengue virus neutralizing antibodies. Lanzavecchia, Antonio. (Institute for Research In
Biomedicine, Switz.). PCT Int. Appl. (2010), 47pp. CODEN: PIXXD2 WO 2010043977 A2
20100422 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG,
PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR,
BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application:
WO 2009-IB7372 20091013. Priority: US 2008-104911 20081013. CAN 152:499422 AN
2010:503823 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The authors disclose the prepn. and characterization of antibodies and antigen-binding fragments that
neutralize dengue virus infection without contributing to antibody-dependent enhancement of dengue
virus infection.
12- Preparation of nucleoside cyclic phosphates as antiviral agents. Du, Jinfa; Nagarathnam,
Dhanapalan; Pamulapati, Ganapati Reddy; Ross, Bruce S.; Sofia, Michael Joseph. (Pharmasset, Inc.,
USA). U.S. Pat. Appl. Publ. (2010), 73pp.; Chemical Indexing Equivalent to 152:57501 (WO).
49
CODEN: USXXCO US 2010081628 A1 20100401 Patent written in English. Application: US
2009-479075 20090605. Priority: US 2008-60683 20080611; US 2008-140369 20081223; US
2008-140317 20081223. CAN 152:381685 AN 2010:406750 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
Cyclic phosphate of nucleoside derivs. I, were prepd., wherein R1 is H, alkyl, cycloalkyl, alkaryl, aryl,
halo-alkyl, halo-alkenyl, halo-alkynyl, alkoxy, halo-alkoxy, CO2H, carboxylate, CONH2, substituted
amide, CH=CHCO2H, CH=CH-carboxylate; R2 is H, alkyl, CN, Me, vinyl, O-alkyl, OMe, OEt,
hydroxy-alkyl, CHwF, N3, CH2CN, CH2N3, CH2NH2, CH2NHMe, CH2NMe2, ethynyl-alkyne,
halogen; R3 is H, Me, CH2F, CHF2, CF3, F, CN; X is H, OH, F, OMe, halogen, NH2, N3; B is
nucleobase; were prepd. and used for the treatment of viral infections in mammals, which is a compd.,
its stereoisomers, salts (acid or basic addn. salts), hydrates, solvates. Thus, nucleotide II was prepd.
and used as antiviral agent.
13- Novel imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity.
Block, Timothy M.; Chang, Jinhong; Xu, Xiaodong. (Institute for Hepatitis and Virus Research,
USA). PCT Int. Appl. (2010), 29pp. CODEN: PIXXD2 WO 2010027996 A1 20100311
Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,
GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU,
LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM. Designated States RW: AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2009-US55658 20090902. Priority: US 2008-190618 20080902. CAN 152:327087 AN
2010:306482 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogs that selectively inhibit cellular α-
glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad
spectrum antiviral activities against many enveloped viruses. To develop' imino sugars with more
potent antiviral activity as well as improved toxicity profile, OSL-9511 (N-pentyl(1-
hydroxycyclohexyl)-DNJ) was modified by diversifying the nitrogen linked alkylated side chain.
Furthermore, these new compds. were shown to be active against Dengue virus (DV) and West Nile
50
virus (WNV) infection in BHK cells with potent anti-DV activity having submicromolar EC50 values
and SI of greater than 900. These compds. represent a new generation of imino sugars and their
analogs, having IS application in the clin. treatment of infection by DV and other members of
flaviviridae.
14- preparation of alkynyl nucleoside analogs for use as antivirals treating HCV and Dengue
viruses. Chen, Yen Liang; Duraiswamy, Jeyaraj; Haller, Sarah; Keim, Matthias; Kondreddi,
Ravinder Reddy; Yin, Zheng. (Novartis AG, Switz.). PCT Int. Appl. (2010), 121pp. CODEN:
PIXXD2 WO 2010015643 A1 20100211 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ,
BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC,
EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA,
NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,
TJ, TM. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC,
MT, NL, NO, PT, SE, SM, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent
written in English. Application: WO 2009-EP60125 20090804. Priority: EP 2008-161933
20080806. CAN 152:239231 AN 2010:179470 CAPLUS (Copyright (C) 2010 ACS on SciFinder
(R))
Abstract
Title compds. I, wherein X is CH or an optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, halogen, cyano, nitro, hydroxy, alkoxy, alkylthio, amino, alkylamino,
carboxy, carboxamide or alkyloxycarbonyl carbon atom; R1 is halogen, (un)substituted amine, or an
(un)substituted ether; R2 is H, halogen, or an (un)substituted amine; R3 is H, alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or
more substituents; R4 is H, acyl or an amino acid ester; R5 is H, acyl or an amino acid ester are prepd.
as antiviral prodrugs. Thus, II was prepd. and demonstrated a dose response inhibition with a dosage
of 32mg/kg bid giving a redn. of viremia of 113 fold. Further, I can be successfully employed as
prodrugs treating Flaviviridae family viral infections selected from the group consisting of dengue
virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus,
Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine
diarrhea virus, Zika virus and Hepatitis C virus. Finally, selected compds. were analyzed for their X-
ray powder diffraction patterns, IR spectrum, differential scanning calorimetry thermograms and
thermogravimetric anal. curve to enhance the most practical method of pharmaceutical drug delivery.
51
15- Preparation of alkynyl nucleoside analogs for use as antivirals treating HCV and Dengue
viruses. Chen, Yen-Liang; Duraiswamy, Jeyaraj; Kondreddi, Ravinder Reddy; Yin, Zheng.
(Novartis AG, Switz.). PCT Int. Appl. (2010), 120pp. CODEN: PIXXD2 WO 2010015637 A1
20100211 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG,
PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, SM, TR,
BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application:
WO 2009-EP60114 20090804. Priority: EP 2008-161941 20080806. CAN 152:239230 AN
2010:179431 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Title compds. I, wherein X is CH or an optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, halogen, cyano, nitro, hydroxy, alkoxy, alkylthio, amino, alkylamino,
carboxy, carboxamide or alkyloxycarbonyl carbon atom; R1 is halogen, (un)substituted amine, or an
(un)substituted ether; R2 is H, halogen, or an (un)substituted amine; R3 is H, alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or
more substituents; R4 is H or a halogen are prepd. as antiviral prodrugs. Thus, II was prepd. and
tested for its cell-based Flavivirus immunodetection assay, HCV replication assay, for activity against
dengue infection and a clin. trial protocol (no data). Further, I can be successfully employed as
prodrugs treating Flaviviridae family viral infections selected from the group consisting of dengue
virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus,
Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine
diarrhea virus, Zika virus and Hepatitis C virus.
16- Method for preparing anti-dengue virus oral preparation from magnetic alginate sodium
drug loaded microspheres. Huang, Yunqing. (Peop. Rep. China). Faming Zhuanli Shenqing
Gongkai Shuomingshu (2010), 20pp. CODEN: CNXXEV CN 101632688 A 20100127 Patent
written in Chinese. Application: CN 2008-10134202 20080721. Priority: . CAN 152:271275 AN
2010:129001 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
CN 101632688 A 20100127 CN 2008-10134202 20080721
Priority Application
52
CN 2008-10134202 20080721
Abstract
The method comprises prepg. water sol. Chinese medicine inclusion microsphere fines, prepg. alc. sol.
Chinese medicine inclusion microsphere fines, mixing two fines, processing to obtain capsules or
tablets. The water sol. Chinese medicine inclusion microsphere is prepd. by mixing β-cyclodextrin,
hypericin, Buffalo Horn ext. and Carapax Amydae ext. together in agitator under frequency of 50-200
r/min for 5-15 min, adding Fe3O4 powder, stirring for 30-90 min, setting the frequency to 50-500
r/min, stirring, adding water, stirring to obtain slurry, adding the slurry in supermol. envelope machine,
hydrating under frequency of 1000-3000 r/min for 30-120 min, drying at 40-65ϒ for 24 h and
pulverizing. The alc. sol. Chinese medicine inclusion microsphere is prepd. by mixing β-cyclodextrin
and artemisinin together in agitator under frequency of 50-200 r/min for 5-15 min, adding Fe3O4
powder, stirring for 30-90 min, setting the frequency to 50-500 r/min, stirring, adding 50-95% ethanol,
stirring to obtain slurry, adding the slurry in supermol. envelope machine, hydrating under frequency
of 1000-3000 r/min for 30-120 min, drying at 40-65ϒ for 24 h and pulverizing. The obtained anti-
dengue virus oral prepn. is used to treating sepsis by resisting dengue fever virus DNA replication and
RNA transcription.
17- Preparation of nucleoside phosphoramidate prodrugs as antiviral agents. Sofia, Michael
Joseph; Du, Jinfa; Wang, Peiyuan; Nagarathnam, Dhanapalan. (Pharmasset, Inc., USA). U.S. Pat.
Appl. Publ. (2010), 77pp.; Chemical Indexing Equivalent to 149:426212 (WO). CODEN:
USXXCO US 2010016251 A1 20100121 Patent written in English. Application: US 2008-
53015 20080321. Priority: US 2007-909315 20070330; US 2007-982309 20071024. CAN
152:144974 AN 2010:85102 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Disclosed herein are nucleoside phosphoramidates prodrugs I, wherein R and R3 are independently H,
alkyl, cycloalkyl, alkylamine, hydroxyalkyl, CH2SH, alkyl-sulfonyl, (CH2)3NHC(=NH)NH2, (1H-
indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, acyl, aryl, aryl-alkyl; R3 and R both are alkyl; R3 and R
together are alkylidene so as to form a spiro ring; R3 is H and R and R2 together are (CH2)n so as to
form a cyclic ring that includes the adjoining N and C atoms; R is H and R3 and R2 together are
(CH2)n. so as to form a cyclic ring; that includes the adjoining N and C atoms, n is 2 to 4; one of R
and R3 is H and the other is R3 CH3, Et, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph,
CH2-indol-3-yl, -CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2,
CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3,
53
CH2((4'-OH)-Ph), CH2SH, cycloalkyl; R1 is H, alkyl, cycloalkyl, aryl; R2 is H, alkyl; R, R2 and R3
together are (CH2)n; R4 is H, alkyl, alkoxy, alkylamino, halo, halo-alkyl, cycloalkyl, aminoacyl, aryl,
heterocycle; R5 is H, alkyl, CN, vinyl, hydroxy-alkyl, CH2OH, CH2F, CH2CN, CH2NH2,
CH2NHMe, CH2NMe2, alkyne; R6 is H, Me, CH2F, CHF2, CF3, F, CN; X is H, OH, F, OMe,
halogen, NH2, N3; Y is OH, H, alkyl, alkenyl, alkynyl, vinyl, N3, CN, halo, oxycarbonyl sulfonyl,
were prepd. and tested as antiviral agents. Thus, nucleoside II was prepd. and tested as antiviral agent
for the treatment of any condition the result of an infection by hepatitis C virus, West Nile virus,
yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus
or Japanese encephalitis virus.
18- Method to control dengue viruses in humans by picolinic acid and derivatives thereof.
Fernandez-Pol, Jose Alberto; Fernandez-Pol, Sebastian. (USA). U.S. Pat. Appl. Publ. (2010),
21pp. CODEN: USXXCO US 2010015174 A1 20100121 Patent written in English. Application:
US 2008-175277 20080717. Priority: . CAN 152:160987 AN 2010:84916 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20100015174 A1 20100121 US 2008-175277 20080717
AR 72542 A1 20100908 AR 2009-102484 20090702
Priority Application
US 2008-175277 A 20080717
Abstract
A method treats and then prevents a virus for afflicting an animal or a human as a metalloprotein
mediates the virus. The method administers systemically a therapeutic pharmacol. agent of picolinic
acid either singly or with interferons, chemokines or cytokines to fight dengue fever virus. The
picolinic acid inactivates the metalloprotein that allows replication of the virus. The invention also
includes the use of picolinic acid derivs. The viral proteins disintegrate by macrophage proteolytic
enzymes stimulated by the picolinic acid.
54
2009 – 22 patents
1- Compositions and methods for Dengue virus (DV) treatment and vaccination. Shresta,
Sujan; Yauch, Lauren E.; Sette, Alessandro. (La Jolla Institute for Allergy and Immunology, USA).
PCT Int. Appl. (2009), 77 pp. CODEN: PIXXD2 WO 2009152147 A2 20091217 Designated
States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN,
CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS,
RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM,
GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2009-US46740
20090609. Priority: US 2008-60088 20080609. CAN 152:72884 AN 2009:1570230 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention relates to Dengue virus peptides and compns. thereof, and methods that employ Dengue
virus peptides and compns. thereof. The peptides include a portion of Dengue virus structural (core,
membrane or envelope) or non-structural (NS1, NS2A, NS2B, NS3, NS4A, NS4B or NS5)
polypeptide sequence eliciting a CD8+ T cell response against a DENV1, DENV2, DENV3 or
DENV4 serotype. The invention includes among other things, methods of treating Dengue virus
infection or pathol., which include, for example, administering Dengue virus peptide T cell epitope, to
treat a Dengue virus infection or pathol. The invention includes among other things Dengue virus
vaccination and immunization methods.
2- Preparation of nucleoside cyclic phosphates as antiviral agents. Du, Jinfa; Nagarathnam,
Dhanapalan; Pamulapati, Ganapati Reddy; Ross, Bruce S.; Sofia, Michael Joseph. (Pharmasset, Inc.,
USA). PCT Int. Appl. (2009), 145pp.; Chemical Indexing Equivalent to 152:381685 (US).
CODEN: PIXXD2 WO 2009152095 A2 20091217 Designated States W: AE, AG, AL, AM, AO,
AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX,
MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL,
SM, ST, SV, SY, TJ, TM. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG.
Patent written in English. Application: WO 2009-US46619 20090608. Priority: US 2008-60683
55
20080611; US 2008-140369 20081223; US 2009-479075 20090605. CAN 152:57501 AN
2009:1565702 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Cyclic phosphate of nucleoside derivs. I, wherein R1 is H, alkyl, cycloalkyl, alkaryl, aryl, halo-alkyl,
halo-alkenyl, halo-alkynyl, alkoxy, halo-alkoxy, CO2H, carboxylate, CONH2, substituted amide,
CH=CHCO2H, CH=CH-carboxylate; R2 is H, alkyl, CN, Me, vinyl, O-alkyl, OMe, OEt, hydroxy-
alkyl, CHwF, N3, CH2CN, CH2N3, CH2NH2, CH2NHMe, CH2NMe2, ethynyl-alkyne, halogen; R3
is H, Me, CH2F, CHF2, CF3, F, CN; X is H, OH, F, OMe, halogen, NH2, N3; B is nucleobase; were
prepd. and used for the treatment of viral infections in mammals, which is a compd., its stereoisomers,
salts (acid or basic addn. salts), hydrates, solvates. Thus, nucleotide II was prepd. and used as antiviral
agent.
3- Application of palmatine in preparing medicine for treating dengue virus infection. Yuan,
Zhiming; Jia, Fan; Zou, Gang; Li, Jing; Shi, Peiyong; Zheng, Dasheng; Cai, Quanxin; Yan, Jianping.
(Wuhan Institute of Virology, Chinese Academy of Sciences, Peop. Rep. China). Faming Zhuanli
Shenqing Gongkai Shuomingshu (2009), 10pp. CODEN: CNXXEV CN 101596192 A
20091209 Patent written in Chinese. Application: CN 2009-10063164 20090714. Priority: . CAN
152:67596 AN 2009:1551932 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
CN 101596192 A 20091209 CN 2009-10063164 20090714
Priority Application
CN 2009-10063164 20090714
Abstract
The invention relates to application of palmatine in prepg. medicine for treating or preventing dengue
virus infection. Palmatine can effectively inhibit dengue virus and has little cytotoxicity.
4- PIP-2 inhibition-based antiviral and anti-hyperlipidemic therapies. Glenn, Jeffrey S.; Cho,
Nam-Joon; Pang, Phillip S.; Lee, Choongho. (Leland Stanford Junior University, USA). PCT Int.
Appl. (2009), 58pp. CODEN: PIXXD2 WO 2009148541 A1 20091210 Designated States W:
AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
56
IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE,
SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE, CH, CY, DE, DK, ES,
FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML,
MR, NE, SN, TD, TG. Patent written in English. Application: WO 2009-US3271 20090529.
Priority: US 2008-57188 20080529. CAN 152:1807 AN 2009:1536387 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Abstract
Interaction of a specific viral domain with phosphatidylinositol 4,5-bisphosphate (PIP 2) is shown to
mediate viral replication. Basic Amino Acid PIP-2 Pincer (BAAPP) domains are described herein,
including, without limitation, NS5A protein of HCV, NS4B protein of HCV, poliovirus, and
rhinovirus.
5- Enhanced antiviral therapy methods and devices comprising lectin affinity hemodialysis.
Tullis, Richard H.; Handley, Harold H., Jr.; Duffin, R. Paul; Joyce, James A. (Aethlon Medical Inc.,
USA). PCT Int. Appl. (2009), 60pp. CODEN: PIXXD2 WO 2009149179 A2 20091210
Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,
GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU,
LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT,
RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN. Designated States RW: AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2009-
US46123 20090603. Priority: US 2008-58536 20080603. CAN 152:27282 AN 2009:1536373
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Embodiments of the present invention relate to enhanced antiviral therapy methods, devices, and kits
for treating viral infections. The disclosed enhanced antiviral therapy methods, devices, and kits
enhance the efficacy of an antiviral therapy by administering a lectin affinity hemodialysis treatment
to an individual suffering from viral infection in combination with the antiviral therapy. A patient
suffering from HCV infection was administered a lectin affinity hemodialysis treatment for 8 h a day,
3 times a week for 12 wk. The viral load of the patient reduced significantly compared to the
administration of the interferon/ribavirin therapy alone, and the patient achieved a sustained viral
response after 12 wk of lectin affinity hemodialysis treatment.
57
6- Small molecule inhibitors for the treatment or prevention of dengue virus and other viral
infection. Byrd, Chelsea M.; Jordan, Robert; Dai, Dongcheng; Hruby, Dennis E. (Siga
Technologies, Inc., USA). PCT Int. Appl. (2009), 88pp. CODEN: PIXXD2 WO 2009149054
A1 20091210 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW,
BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD,
GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR,
LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG,
PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN. Designated States
RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR,
BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application:
WO 2009-US45921 20090602. Priority: US 2008-58263 20080603. CAN 152:27275 AN
2009:1532703 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Methods and pharmaceutical compns. for treating viral infections, by administering certain compds. in
therapeutically effective amts. are disclosed. Methods of using the compds. and pharmaceutical
compns. thereof are also disclosed. In particular, the treatment and prophylaxis of viral infections
such as caused by flavivirus is disclosed, i.e., including but not limited to, Dengue virus, West Nile
virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. A compd.
library was screened for inhibitory activity against dengue virus-induced cytopathic effect on Vero
cells. Active compds. were tested for activity in viral yield assays carried out at several drug concns.
I was one of the most potent and selective compds. from the pool of initial 22 quality hits, with
activity against all four serotypes of dengue virus. Hard gelatin capsules contain active ingredient
30.0, starch 305.0, and magnesium stearate 5.0 mg/capsule.
7- Preparation of 1'-substituted carba-nucleoside analogs as antiviral agents. Butler, Thomas;
Cho, Aesop; Kim, Choung U.; Saunders, Oliver L.; Zhang, Lijun. (Gilead Sciences, Inc., USA).
PCT Int. Appl. (2009), 173pp. CODEN: PIXXD2 WO 2009132135 A1 20091029 Designated
States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO,
CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU,
ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC,
SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM,
GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2009-US41447
58
20090422. Priority: US 2008-47263 20080423; US 2008-139449 20081219. CAN 151:470463
AN 2009:1325388 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
1'-Substituted carba-nucleoside analogs I, wherein R1-R5 are independently H, OR, NR2, N3, CN,
NO2, S(O)nR, halogen, alkyl, carbocyclyl-alkyl, alkenyl, alkynyl, arylalkyl; any two of R1-R5 on
adjacent carbo when taken together are O(CO)O or when taken together with the ring carbon to which
they are attached form a double bond; R6 is id OR, NR2, N3, CN, NO2, S(O)nR, acyl, carboxylate,
amide, thio ester, sulfonyl, sulfonamide, halogen, alkyl, carbocyclyl-alkyl, alkylalkenyl, alkenyl,
alkynyl, arylalkyl; R1R6 or R2R6 together form O(CO)O; n is 0-2; R is H, alkyl, alkenyl, alkynyl,
arylalkyl, carbocyclyl-alkyl, acyl, carboxylate ester, amide, thio ester, sulfonyl, sulfonamide; R7 is H,
acyl, carboxylate ester, amide, sulfonyl, sulfonamide, substituted phosphorus; R8 is halogen,
substituted N, N3, NO, NO2, CHO, CN, imine, oxime, ketal, amide, sulfonamide, carboxylate ester,
alkyl, alkenyl, alkynyl, carbocycloalkyl; R9 and R10 are independently H, halogen, substituted N, N3,
NO, substituted hydrazine, NO2, CHO, CN, imine, oxime, ketal, amide, thioamide, carboxylate ester,,
were prepd. and used as antiviral agents. The compds., compns., and methods provided are useful for
the treatment of Flaviviridae virus infections, particularly hepatitis C infections. Thus, nucleoside II
was prepd. and tested as antiviral agent (EC50 10-100 μM), wherein the viral infection is caused by a
virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese
encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St.
Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and
Hepatitis C virus.
8- Preparation of 1'-substituted carba-nucleoside analogs as antiviral agents carba-nucleoside
analogs for antiviral treatment. Cho, Aesop; Kim, Choung U.; Parrish, Jay; Xu, Jie. (Gilead
Sciences, Inc., USA). PCT Int. Appl. (2009), 154pp. CODEN: PIXXD2 WO 2009132123 A1
20091029 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2009-US41432 20090422. Priority: US 2008-47263 20080423; US 2008-139449 20081219. CAN
151:491358 AN 2009:1325387 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
59
Abstract
1'-Substituted carba-nucleoside analogs I, wherein R1-R5 are independently H, OR, NR2, N3, CN,
NO2, S(O)nR, halogen, alkyl, carbocyclyl-alkyl, alkenyl, alkynyl, arylalkyl; any two of R1-R5 on
adjacent carbo when taken together are O(CO)O or when taken together with the ring carbon to which
they are attached form a double bond; R6 is id OR, NR2, N3, CN, NO2, S(O)nR, acyl, carboxylate,
amide, thio ester, sulfonyl, sulfonamide, halogen, alkyl, carbocyclyl-alkyl, alkylalkenyl, alkenyl,
alkynyl, arylalkyl; R1R6 or R2R6 together form O(CO)O; n is 0-2; R is H, alkyl, alkenyl, alkynyl,
arylalkyl, carbocyclyl-alkyl, acyl, carboxylate ester, amide, thio ester, sulfonyl, sulfonamide; R7 is H,
acyl, carboxylate ester, amide, sulfonyl, sulfonamide, substituted phosphorus; R8 is halogen,
substituted N, N3, NO, NO2, CHO, CN, imine, oxime, ketal, amide, sulfonamide, carboxylate ester,
alkyl, alkenyl, alkynyl, carbocycloalkyl; R9 and R10 are independently H, halogen, substituted N, N3,
NO, substituted hydrazine, NO2, CHO, CN, imine, oxime, ketal, amide, thioamide, carboxylate ester,,
were prepd. and used as antiviral agents. The compds., compns., and methods provided are useful for
the treatment of Flaviviridae virus infections, particularly hepatitis C infections. Thus, nucleoside II
was prepd. and tested as antiviral agent (EC50 10-100 μM), wherein the viral infection is caused by a
virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese
encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St.
Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and
Hepatitis C virus.
9- Chemical compounds having antiviral activity against dengue virus and other flaviviruses.
Mazola Reyes, Yuliet; Chinea Santiago, Glay; Guirola Cruz, Osmany; Vera Alvarez, Roberto; Huerta
Galindo, Vivian; Fleitas Salazar, Noralvis; Musacchio Lasa, Alexis. (Centro de Ingenieria Genetica y
Biotecnologia, Cuba). PCT Int. Appl. (2009), 81pp. CODEN: PIXXD2 WO 2009106019 A2
20090903 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in Spanish. Application: WO
2009-CU2 20090227. Priority: CU 2008-28 20080229. CAN 151:280183 AN 2009:1082068
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
60
Abstract
The invention relates to the use of chem. compds. obtained in silico for the prepn. of pharmaceutical
compns. for attenuating or inhibiting dengue virus infection, in particular by interference with or
modulation of the multiple steps of the viral replication cycle assocd. with the arrival of the virus in
the target cells and the assembly of the progeny virions. The invention also relates to the use of said
pharmaceutical compns. for the prophylactic or therapeutic treatment of infection caused by the four
dengue virus serotypes and by other flaviviruses. The compds. are composed of two functional
subunits denoted, [C]-[A]. Where [A] is an anchor capable of latching on to the lj loop of protein E.
The anchor may be a hydrogen donor, a hydrogen acceptor, a hydrophobic element, a hydrogen donor
and acceptor simultaneously. The "head" subunit, or [C], contains the antiviral activity and it is
covalently attached to subunit [A].
10- Development of a broad-spectrum antiviral with activity against Ebola virus. Aman, M.
Javad; Kinch, Michael S.; Warfield, Kelly; Warren, Travis; Yunus, Abdul; Enterlein, Sven; Stavale,
Eric; Wang, Peifang; Chang, Shaojing; Tang, Qingsong; Porter, Kevin; Goldblatt, Michael; Bavari,
Sina. United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, MD,
USA. Antiviral Research (2009), 83(3), 245-251. Publisher: Elsevier B.V., CODEN: ARSRDR
ISSN: 0166-3542. Journal written in English. CAN 151:417551 AN 2009:1001305 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
We report herein the identification of a small mol. therapeutic, FGI-106, which displays potent and
broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley
and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further
demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a
prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient
to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory
activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a
common pathway utilized by different viruses. These findings suggest FGI-106 may provide an
opportunity for targeting viral diseases.
11- Methods of inhibiting viral infection. Kinch, Michael; Goldblatt, Michael. (Functional
Genetics, Inc., USA). PCT Int. Appl. (2009), 65pp. CODEN: PIXXD2 WO 2009091435 A2
20090723 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
61
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2008-US81904 20081031. Priority: US 2007-983966 20071031. CAN 151:189938 AN
2009:885111 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Compds., pharmaceutical compns. and methods of inhibiting viral infection in a mammal in need of
same, are provided, which employ quinoline compds. This family of compds., designated FGI-104
herein, inhibits viral infection therapeutically and prophylactically.
12- An astragalus extract as an antiviral for several genera of the flaviviridae family. Zhong,
Shouming; Yu, Hongwen; Blair, Edward. (Phynova Limited, UK). PCT Int. Appl. (2009), 89pp.;
Chemical Indexing Equivalent to 151:16632 (GB). CODEN: PIXXD2 WO 2009068872 A1
20090604 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2008-GB3947 20081126. Priority: GB 2007-23609 20071127. CAN 151:16633 AN 2009:669997
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention relates to a novel antiviral product and its use in the treatment of the flaviviridae
family of viruses including the genus flavivirus, particularly Dengue. An antiviral product and its use
in the treatment of the Flaviviridae family of viruses including the genera Flavivirus, particularly
Dengue, Pestivirus, Unassigned Flaviviradae, and tentative Species of the Genus HCV. The antiviral
product is an ext. of Astragalus and preferably comprises at least one marker selected from
astragaloside I, astragaloside IV, formononetin-7-O-β-D-glucoside and 3'-hydroxyl-formononetin-7-O-
β-D-glucoside.
62
13- Dengue virus 2 non-structural protein 2b for preparing DNA vaccines, antibodies, anti-
dengue virus agents and NS2B research. Liu, Limei; An, Jing; Chen, Zongtao. (Third Military
Medical University, PLA, Peop. Rep. China). Faming Zhuanli Shenqing (2009), 24pp. CODEN:
CNXXEV CN 101429236 A 20090513 Patent written in Chinese. Application: CN 2008-
10233216 20081203. Priority: . CAN 151:31759 AN 2009:596452 CAPLUS (Copyright (C)
2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
CN 101429236 A 20090513 CN 2008-10233216 20081203
Priority Application
CN 2008-10233216 20081203
Abstract
The dengue virus type 2 non-structural protein 2B (NS2B) has an amino acid sequence of SEQ ID
No.2. The invention also provides a recombination expression vector and a transformant contg.
NS2B. The recombination expression vector successfully exhibits NS2B in eukaryotic cell, induces
specific anti-NS2B polyclonal antibody in mouse, and can be used for prepg. nucleic acid vaccine
against dengue virus 2 type and anti-NS2B antibody.
14- Antiviral agents containing silver-chloro complex. Yokosawa, Hirotsugu. (Japan). Jpn.
Kokai Tokkyo Koho (2009), 15pp. CODEN: JKXXAF JP 2009096745 A 20090507 Patent
written in Japanese. Application: JP 2007-268414 20071015. Priority: . CAN 150:488982 AN
2009:549478 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
JP 2009096745 A 20090507 JP 2007-268414 20071015
Priority Application
JP 2007-268414 20071015
63
Abstract
The antiviral agents and antiviral method whose effect is maintained, are developed. The antiviral
agents of this invention contains the silver chloro complex so that it may be supplied by the silver
concn. of 2.4-40 mg/L. Surprisingly, it was discovered that when the silver concn. of the silver-chloro
complex soln. is much lower than the concn. range usually used as antibacterial agents (100 - 200
mg/L), it can actualize virus control.
15 - Optimized dengue virus entry inhibitory peptide (DN81). Michael, Scott F.; Isern, Sharon;
Garry, Robert; Samudrala, Ram; Costin, Joshua; Jenwitheesuk, Ekachai. (Florida Gulf Coast
University, USA). PCT Int. Appl. (2009), 19pp. CODEN: PIXXD2 WO 2009048658 A2
20090416 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2008-US69716 20080711. Priority: US 2007-949710 20070713. CAN 150:414217 AN
2009:456348 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention provides peptide entry inhibitors bindable to regions in viral class II E proteins. The
interaction of an inhibitor with such regions, or the modulation of the activity of such regions with an
inhibitor, could inhibit viral fusion and hence viral infectivity. In one aspect, the invention provides
compds. and methods of screening the compds. against these bindable regions in order to discover
therapeutic candidates for a disease caused by a virus having a class II protein. Furthermore, the
invention provides for methods of inhibiting viral infection by dengue virus and/or binding between
the virion envelope of dengue viruses and membranes of the target cell (the process that delivers the
viral genome into the cell cytoplasm). The invention provides for methods that employ peptides or
peptide derivs. to inhibit dengue virus:cell binding. The invention provides for methods of treatment
of diseases induced by the dengue virus. The DN81 peptide showed an increase in inhibitory activity
as a function of concn.
15- Optimized dengue virus entry inhibitory peptide (10AN). Michael, Scott F.; Isern, Sharon;
Costin, Joshua; Samudrala, Ram; Jenwitheesuk, Ekachai. (Florida Gulf Coast University, USA).
PCT Int. Appl. (2009), 19pp. CODEN: PIXXD2 WO 2009045596 A2 20090409 Designated
64
States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO,
CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU,
ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC,
SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM,
GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2008-US69725
20080711. Priority: US 2007-949733 20070713. CAN 150:431673 AN 2009:424610 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention relates to peptide entry inhibitors and methods of detg. such inhibitors that are bindable
to regions of viruses having class II E proteins, such as the dengue virus E protein, as candidates for in
vivo anti-viral compds. Thus, the 10AN peptide having a SEQ ID NO 1:
FWFTLIKTQAKQPARYRRFC showed an increase in inhibitory activity against dengue virus 2
(DENV-2) in vitro as a function of concn., as demonstrated using focus-forming assays.
16- microRNA profiles in the diagnosis of viral infection and the identification of microRNAs as
targets for antiviral therapy. Kowalik, Timothy F.; Stadler, Bradford M. (University of
Massachusetts, USA). PCT Int. Appl. (2009), 194pp. CODEN: PIXXD2 WO 2009033185 A1
20090312 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY,
BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH,
GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2008-US75646 20080908. Priority: US 2007-967780 20070906. CAN 150:304161 AN
2009:292432 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention related to miRNA signatures and diagnostic and therapeutic applications of
miRNA signatures. The miRNA signatures are defined by a test sample miRNA profile relative to an
appropriate control miRNA profile. In some embodiments, the test sample is a sample isolated,
obtained or derived from a virus- infected cell or organism. The present invention further relates to
the use of miRNA signatures in the identification of draggable targets and antiviral agents. Kits and
65
compns. are also provided. The identification of specific miRNA signatures for infection of human
cell lines by adenovirus 5 and human cytomegalovirus.
17- Preparation of acridinone derivatives as antiparasitic, antifungal and antiviral agents.
Pellon Condom, Rolando F.; Docampo Palacios, Maite L.; Pardo Andreu, Gilberto L.; Fernandez
-Calienes Valdes, Ayme; Mendiola Martinez, Barbara Judith; Rojas Rivero, Lazara; D'Accorso Haicck,
Norma Beatriz; Fascio Silva, Mirta Liliana; Damonte Lotito, Elsa Beatriz; Garcia Cattebeke, Cybele
Carina; Sepulveda Suchecki, Claudia Soledad; Mazzucco Gavieiro, Maria Belen; Talarico Salinas,
Laura Beatriz; Maes, Louis. (Centro de Quimica Farmaceutica, Cuba). PCT Int. Appl. (2009),
40pp. CODEN: PIXXD2 WO 2009026858 A1 20090305 Designated States W: AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM,
DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX,
MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM,
ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD,
TG. Patent written in Spanish. Application: WO 2008-CU7 20080828. Priority: CU 2007-202
20070828. CAN 150:283334 AN 2009:259420 CAPLUS (Copyright (C) 2010 ACS on SciFinder
(R))
Abstract
The invention relates to the synthesis and evaluation of novel acridinone derivs. as antiparasitic,
antifungal and antiviral agents. More specifically, the invention relates to 10-allyl-, 10-(3-methyl-2-
butenyl)-, 10-(1,2-propanodienyl)-9(10H)-acridinone, and 10-[[3-[(4R,5R,6S,7R)-6-hydroxy-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4,5-dihydro-5-isoxazolyl]methyl]-9(10H)acridinone
(I) or their derivs. in which positions 1-8 of the acridinone ring may be substituted by halogen,
hydroxy, amino, nitro, alkyl, alkoxy, and other groups. The acridinones have an activity against
Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi protozoans, as well as
Microsporum canis and strains of the Junin virus and Dengue. Thus, acridinone deriv. I was prepd.
from 9-acridinone by allylation followed by cycloaddn. reaction with 1,2-O-isopropylidene-α-D-
xylopentadialdo-1,4-furanose oxime. The possible biol. mode of action of the acridinone derivs. was
studied using 10-allyl-6-chloro-2-fluoro-9(10H)-acridinone as model compd.
66
18- TRAIL antigens in dengue fever and their use as targets in treating dengue virus infection.
Bosch, Irene; Warke, Rajas V.; Martin, Katherine J. (University of Massachusetts Medical School,
USA). PCT Int. Appl. (2009), 145pp. CODEN: PIXXD2 WO 2009025743 A2 20090226
Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,
MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO,
RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2008-
US9666 20080813. Priority: US 2007-965173 20070817. CAN 150:275521 AN 2009:238890
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
TRAIL antigens are shown to play a role in the development of dengue fever, an important tropical
illness for which there is currently no virus-specific treatment, and may therefore be useful in the
treatment of the disease. Gene expression profiling in cultured primary human cells, including human
umbilical vein endothelial cells (HUVECs), dendritic cells (DCs), monocytes and B cells, using the
com. Affymetrix GeneChip (HG-U1 33A), identified changes in response to dengue virus infection.
Tissue necrosis factor-related apoptosis inducing ligand (TRAIL) gene expression was a common
response in all cells and may play a role as an immunomodulator in infected cells. Interactions
between type-I and II interferon response genes and TRAIL are expected to increase the innate
immunity to the virus or even to other pathogens like bacteria. Dengue virus induces TRAIL
expression in immune cells and HUVECs at the mRNA and protein level and was found to be
dependent on an intact interferon type I signaling pathway. Anti-TRAIL antibody incubation with
primary cells showed an increase in dengue virus accumulation and conversely, a decrease in viral
RNA when TRAIL was added to the culture. These data suggest that TRAIL may play a role in the
anti-viral response to dengue fever and that it is a candidate for anti-viral interventions to the disease.
Further, TRAIL antiviral function does not promote apoptosis. The role of exogenous TRAIL in
dendritic cells confirmed a strong anti-inflammatory response due to the lowering of prodn. of
mediators of inflammation present in dengue infection. TRAIL may also be useful in the treatment of
other flavivirus infections.
19- Iminosugar compounds with antiflavivirus activity. Gu, Baohua; Block, Timothy M.;
Moriarty, Robert M.; Deshpande, Mahendra N.; Shah, Rajendra C. (The Board of Trustees of the
University of Illinois, USA). U.S. Pat. Appl. Publ. (2009), 27 pp. CODEN: USXXCO US
67
2009042268 A1 20090212 Patent written in English. Application: US 2008-112694 20080430.
Priority: US 2007-914889 20070430. CAN 150:229640 AN 2009:172500 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20090042268 A1 20090212 US 2008-112694 20080430
Priority Application
US 2007-914889P P 20070430
Abstract
An anti-viral compds. effective against viruses belonging to the Flaviviridae family, wherein the anti-
viral compds. are 1,5-dideoxy-1,5-imino-D-glucitol deriv. compds.
20- Dengue virus nonstructural protein NS1-based methods for identifying agents for treating
dengue hemorrhagic fever. Ikuta, Kazuyoshi; Kurosu, Takeshi; Anantapreecha, Surapee;
Sawanpanyalert, Pathom. (Osaka University, Japan; National Institute of Health (NIH), Department of
Medical Sciences (DMSC); Ministry of Public Health, Nonthaburi). PCT Int. Appl. (2009), 45
pp. CODEN: PIXXD2 WO 2009016831 A1 20090205 Designated States W: AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM,
DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX,
MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM,
ST, SV, SY, TJ, TM, TN, TR. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD,
TG. Patent written in English. Application: WO 2008-JP2035 20080730. Priority: US 2007-
953583 20070802. CAN 150:183353 AN 2009:140200 CAPLUS (Copyright (C) 2010 ACS on
SciFinder (R))
Abstract
Compds. that inhibit the binding of dengue virus nonstructural protein NS1 to complement regulatory
protein clusterin, or that inhibit complement activation by NS1, can be used for treating dengue virus
infection, dengue hemorrhagic fever, and dengue shock syndrome. Such compds. can be identified
using methods that measure inhibition of NS1/clusterin binding, and/or inhibition of complement
activation.
68
21- Fc variants of monoclonal antibodies against dengue and other viruses. Goncalvez, Ana P.;
Purcell, Robert H.; Lai, Ching-Juh. (United States Dept. of Health & Human Services, USA). PCT
Int. Appl. (2009), 95 pp. CODEN: PIXXD2 WO 2009011941 A2 20090122 Designated States
W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR,
CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE,
SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT. Designated States RW: AT, BE, CH, CY, DE, DK, ES,
FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML,
MR, NE, SN, TD, TG. Patent written in English. Application: WO 2008-US59313 20080403.
Priority: US 2007-922282 20070404; US 2007-927755 20070504; US 2007-928405 20070508.
CAN 150:166232 AN 2009:93361 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The authors disclose Fc region variants of antibodies the bind an Fcγ receptor (FcγR) with lower
affinity than the parent antibodies. The variants, targeting the envelope glycoprotein of dengue virus,
are shown to exhibit reduced or absent antibody-dependent enhancement of infection.
22- Antiviral properties of zosteric acid and related molecules. Michael, Scott F.; Isern, Sharon;
Costin, Joshua. (Florida Gulf Coast University, USA). PCT Int. Appl. (2009), 36pp. CODEN:
PIXXD2 WO 2009012157 A2 20090122 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ,
BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG,
NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM,
TN, TR. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC,
MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written
in English. Application: WO 2008-US69808 20080711. Priority: US 2007-949694 20070713; US
2008-58026 20080602. CAN 150:136611 AN 2009:79032 CAPLUS (Copyright (C) 2010 ACS
on SciFinder (R))
Abstract
The invention relates chem. compd. entry inhibitors and methods of detg. such inhibitors that interact
with regions of viruses, such as the dengue virus, as candidates for in vivo antiviral compds. Compds.
of the invention include zosteric acid and related mols.
69
2008 – 8 patents
1- Use of sequence covariance networks for identification of targets for designing antiviral
agents and for diagnostic applications. Aurora, Rajeev; Donlin, Maureen J.; Tavis, John E. (Saint
Louis University, USA). U.S. Pat. Appl. Publ. (2008), 23pp. CODEN: USXXCO US
2008318207 A1 20081225 Patent written in English. Application: US 2008-144030 20080623.
Priority: US 2007-945543 20070621; US 2007-987696 20071113. CAN 150:71091 AN
2008:1532900 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20080318207 A1 20081225 US 2008-144030 20080623
Priority Application
US 2007-945543P P 20070621
US 2007-987696P P 20071113
Abstract
Methods of identifying targets for designing a therapeutic agent are disclosed. These methods
comprise: detg. an amino acid sequence of one or more polypeptides of each isolate of a plurality of
isolates of a biol. system; identifying covariance pairs of amino acid residues; establishing a network
comprising the covariance pairs; and identifying one or more hub residue positions, wherein a hub
residue position comprises a target for designing a therapeutic agent if the hub residue position has a
rank order in the 40th percentile or greater. Methods are disclosed for selecting a therapy for an
infectious disorder, in particular methods for selecting an antiviral therapy. In various configurations,
these methods comprise: detg. amino acids occupying a plurality of diagnostic amino acid residue
positions comprised by one or more polypeptides encoded by an infectious agent infecting a subject;
and assigning the infectious agent infecting the subject to one covariance network selected from a
plurality of covariance networks, wherein each network comprises a unique rank order of hubs with
respect to the other networks, and whereby the therapy is selected on the basis of the covariance
network assignment. The invention also provides methods for designing antimicrobial and antiviral
therapeutic agents, and methods for establishing a differential diagnosis.
70
2- Antiviral drugs for treatment or prevention of dengue infection. Byrd, Chelsea M.; Jordan,
Robert; Dai, Dongcheng; Bolken, Tove; Hruby, Dennis E. (Siga Technologies, Inc., USA). PCT Int.
Appl. (2008), 67pp. CODEN: PIXXD2 WO 2008147962 A1 20081204 Designated States W:
AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE,
SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT. Designated States RW: AT, BE, CH, CY, DE, DK, ES,
FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML,
MR, NE, SN, TD, TG. Patent written in English. Application: WO 2008-US64662 20080523.
Priority: US 2007-924628 20070523. CAN 150:16036 AN 2008:1454478 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Abstract
Compds., methods and pharmaceutical compns. for treating viral infections, by administering certain
compds. in therapeutically effective amts. are disclosed. Methods for prepg. the compds. and methods
of using the compds. and pharmaceutical compns. thereof are also disclosed. In particular, the
treatment and prophylaxis of viral infections such as caused by flavivirus is disclosed, i.e., including
but not limited to, Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and
tick-borne encephalitis virus. The present invention provides a pharmaceutical compn. comprising a
pharmaceutically acceptable carrier and a compd. having the following general formula Ar-SO2-
NR1R2 wherein R1 and R2 are independently hydrogen, alkyl, alkenyl, alkynyl, or unsubstituted or
substituted cycloalkyl, arylalkyl, aryl, or R1 and R2 together may form a substituted or unsubstituted
ring, which may include one or more heteroatoms in the ring; and Ar is substituted or unsubstituted
aryl or heteroaryl.
3- Antiviral amphipathic helical peptides derived from HCV NS5A membrane anchoring
peptide. Chisari, Francis V. (The Scripps Research Institute, USA). PCT Int. Appl. (2008),
242pp. CODEN: PIXXD2 WO 2008133759 A2 20081106 Designated States W: AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM,
DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX,
MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM,
SV, SY, TJ, TM, TN, TR, TT. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IS, IT, LU, MC, MT, NL, NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD,
TG. Patent written in English. Application: WO 2008-US452 20080110. Priority: US 2007-
71
879727 20070110; US 2007-967783 20070907. CAN 149:525347 AN 2008:1338066 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present application is directed to antiviral peptides, methods of using these peptides to prevent or
inhibit infections by a human immunodeficiency virus or a virus from the Flaviviridae family, and
pharmaceutical compns. and combinations, as well as articles of manuf. comprising these peptides. In
particular, an amphipathic alpha-helical peptide derived from the membrane anchor domain of the
Hepatitis C virus (HCV) NS5A protein is identified to inhibit HCV infection by inactivating both
extracellular and intracellular infectious particles. By screening its derived peptide library, more
peptide derivs. or analogs sharing eight consensus amino acid sequences are also identified to be
virocidal in broad range, to flaviviruses, paramyxoviruses, and human immunodeficiency virus. For
HIV, these antiviral peptides prevent its infection by disrupting the integrity of the viral membrane and
capsid core while preserving the integrity of host membranes.
4- Preparation of nucleoside phosphoramidate prodrugs as antiviral agents. Sofia, Michael J.;
Du, Jinfa; Wang, Peiyuan; Nagarathnam, Dhanapalan. (Pharmasset, Inc., USA). PCT Int. Appl.
(2008), 751 pp., Chemical Indexing Equivalent to 152:144974 (US). CODEN: PIXXD2 WO
2008121634 A2 20081009 Designated States W: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG,
BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL,
NO, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2008-US58183 20080326. Priority: US 2007-909315 20070330; US 2007-
982309 20071024; US 2008-53015 20080321. CAN 149:426212 AN 2008:1215396 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Disclosed herein are nucleoside phosphoramidates prodrugs I, wherein R and R3 are independently H,
alkyl, cycloalkyl, alkylamine, hydroxyalkyl, CH2SH, alkyl-sulfonyl, (CH2)3NHC(=NH)NH2, (1H-
indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, acyl, aryl, aryl-alkyl; R3 and R both are alkyl; R3 and R
together are alkylidene so as to form a spiro ring; R3 is H and R and R2 together are (CH2)n so as to
form a cyclic ring that includes the adjoining N and C atoms; R is H and R3 and R2 together are
(CH2)n. so as to form a cyclic ring; that includes the adjoining N and C atoms, n is 2 to 4; one of R
and R3 is H and the other is R3 CH3, Et, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph,
72
CH2-indol-3-yl, -CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2,
CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3,
CH2((4'-OH)-Ph), CH2SH, cycloalkyl; R1 is H, alkyl, cycloalkyl, aryl; R2 is H, alkyl; R, R2 and R3
together are (CH2)n; R4 is H, alkyl, alkoxy, alkylamino, halo, halo-alkyl, cycloalkyl, aminoacyl, aryl,
heterocycle; R5 is H, alkyl, CN, vinyl, hydroxy-alkyl, CH2OH, CH2F, CH2CN, CH2NH2,
CH2NHMe, CH2NMe2, alkyne; R6 is H, Me, CH2F, CHF2, CF3, F, CN; X is H, OH, F, OMe,
halogen, NH2, N3; Y is OH, H, alkyl, alkenyl, alkynyl, vinyl, N3, CN, halo, oxycarbonyl sulfonyl,
were prepd. and tested as antiviral agents. Thus, nucleoside II was prepd. and tested as antiviral agent
for the treatment of any condition the result of an infection by hepatitis C virus, West Nile virus,
yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus
or Japanese encephalitis virus.
5- Method using pigs for the evaluation of dengue virus antiviral agents and vaccines.
Burgess, Timothy H.; Porter, Kevin R.; Freilich, Daniel A.; Doolan, Denise L. (USA). U.S. Pat.
Appl. Publ. (2008), 10pp. CODEN: USXXCO US 2008219930 A1 20080911 Patent written in
English. Application: US 2006-507322 20060821. Priority: US 2005-709804 20050822. CAN
149:299778 AN 2008:1098279 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20080219930 A1 20080911 US 2006-507322 20060821
Priority Application
US 2005-709804P P 20050822
Abstract
The invention discloses a method for evaluating potential compds. and vaccines for the prevention or
treatment of dengue virus infection. The method utilizes pigs as an animal model for the evaluation of
test vaccine or drug compds. The breeds that can be used include Yorkshire or Lancashire, as well as
miniature pig breeds.
6- A dengue reporter virus and methods of producing and using it to identify dengue virus
inhibitors. Puffer, Bridget; Doranz, Benjamin J. (Integral Molecular, Inc., USA). PCT Int. Appl.
(2008), 57 pp. CODEN: PIXXD2 WO 2008051266 A2 20080502 Designated States W: AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK,
73
DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, ME, MG, MK, MN, MW,
MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL,
SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI,
FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN,
TD, TG. Patent written in English. Application: WO 2007-US3660 20070212. Priority: US
2006-772916 20060213. CAN 148:487140 AN 2008:529145 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
The invention relates to the prodn. and uses of dengue virus replicons and dengue reporter virus
particles. The invention relates to methods for identifying inhibitors of dengue virus infection,
inhibitors of dengue virus replication, and inhibitors of dengue virus assembly.
7- Preparation of D-glucopyranose 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate] as antiviral
agent. Vachy, Robert. (RDW Pharma, Fr.). PCT Int. Appl. (2008), 18pp. CODEN: PIXXD2
WO 2008000920 A1 20080103 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG,
BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD,
GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT,
SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in French.
Application: WO 2006-FR1486 20060623. Priority: . CAN 148:79261 AN 2008:12161
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
D-glucopyranose 1-[3,5-bis(1,1-dimethyl-ethyl)-4-hydroxybenzoate] was prepd. by glycosylation of
3,5-bis(t-Bu)-4-hydroxybenzoic acid with D-glucose. It applies in particular to the prepn. and the use
of this compd. and of its derivs. for the prepn. of medicaments for the treatment and/or prevention of
infections with enveloped viruses, and in particular, in humans, the Herpes virus, the AIDS virus, the
flu virus, the hepatitis B virus, the hepatitis C virus, the dengue virus and the Ebola virus.
8- Mitochondrial antiviral signaling protein in the prevention and treatment of viral diseases.
Chen, Zhijian; Bhargava, Rashu Seth; Sun, Lijun; Li, Xiao-Dong. (Board of Regents, The University
of Texas System, USA). U.S. Pat. Appl. Publ. (2008), 93pp. CODEN: USXXCO US
2008003614 A1 20080103 Patent written in English. Application: US 2006-509924 20060825.
74
Priority: US 2005-711451 20050825. CAN 148:142884 AN 2008:9095 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20080003614 A1 20080103 US 2006-509924 20060825
US 7625724 B2 20091201
US 20100137562 A1 20100603 US 2009-628509 20091201
Priority Application
US 2005-711451P P 20050825
US 2006-509924 A3 20060825
Abstract
The present invention includes the identification and characterization of a novel protein designated
mitochondrial antiviral signaling (MAVS) that is essential for NF-κB and IRF3 activation by RNA
viruses. MAVS includes an N-terminal CARD-like domain and a C-terminal transmembrane domain
that targets the protein to the mitochondrial membrane. MAVS functions downstream of RIG-1 and
upstream of IκB and IRF3 phosphorylation. Suppression of MAVS expression blocks interferon
prodn. and exacerbates the viral replication and killing of the host cells. Conversely, overexpression
of MAVS augments interferon prodn. and confers antiviral immunity. Deletion of the CARD-like
domain of MAVS abolishes its signaling function and converts it into a dominant neg. mutant that
inhibits interferon induction. MAVS is cleaved at Cys-508 by the hepatitis C virus NS3/4A protease.
These results reveal a new role of mitochondria in innate immunity, and provide new compn. and
methods for diagnosis and treatment of viral infection and methods of high-throughput screening for
antiviral compds.
75
2007 – 11 patents
1- Kalata B1-based peptides for inhibition of viral NS3 protease. Cui, Taian; Puah, Chum Mok;
Liew, Oi Wah; Lee, Siew Hui. (Singapore Polytechnic, Singapore). PCT Int. Appl. (2007), 56pp.
CODEN: PIXXD2 WO 2007149052 A1 20071227 Designated States W: AE, AG, AL, AM, AT,
AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN,
KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA,
NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM,
TN, TR, TT, TZ, UA. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS,
IT, LU, MC, MT, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent
written in English. Application: WO 2007-SG168 20070619. Priority: SG 2006-4180 20060619.
CAN 148:115525 AN 2007:1469276 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Kalata B1-based peptides comprising viral NS3 serine protease recognition sequence on a cyclic mol.
framework for use as anti-virals in the treatment of dengue fever are disclosed. Thus, the peptides
were produced as fusion proteins with His-tagged thioredoxin in transgenic E. coli. After purifn. with
a metal-chelating column the antiviral peptide was released from the fusion protein by enterokinase
cleavage.
2- Inhibition of RNA virus replication using suicide gene- or toxin-encoding viral vector, for use
in prevention or treatment of viral infections in humans. Ventura, Michel; Astier-Gin, Therese;
Litvak, Simon; Dumas, Estelle. (Universite Victor Segalen- Bordeaux 2, Fr.; Centre National Da La
Recherche Scientifique - Cnrs). PCT Int. Appl. (2007), 66pp. CODEN: PIXXD2 WO
2007138193 A1 20071206 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH,
BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB,
GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL,
PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in French.
Application: WO 2007-FR899 20070530. Priority: FR 2006-4806 20060530. CAN 148:45774
AN 2007:1394359 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
76
Abstract
This invention relates to gene therapy for viral infections using a hepatitis C virus (HCV) viral vector
comprising 5'- and 3'-untranslated region (UTR) sequences flanking either a suicide gene or a gene
encoding a toxin, to enable cell death in cells expressing the complete viral replication complex.
Replication of single stranded genomic RNA viruses (such as HCV) requires an intermediate step of
synthesis of the neg. single-strand viral genome, which serves as template for synthesis of the pos.
single-strand virus. For this step of replication, the 5'-UTR and 3'-UTR are indispensable; the 3'-UTR
is responsible for synthesis of the neg. strand from the pos. strand, and the 5'-UTR is responsible for
synthesis of the pos. strand for new virions from the neg. strand template. A genomic fragment contg.
the HCV nonstructural protein genes (NS3-NS5B) was transformed into Huh7 cells. Further a viral
vector was produced that substituted the HCV polyprotein gene (flanked by 5'- and 3'-UTR; the
minimal HCV genomic RNA), with genes encoding the hygromycin resistance protein, FMDV protein
2A, and enhanced green fluorescent protein. The resulting viral vector, 5'-UTR-Hygror-H2AE-EGFP-
3'-UTR, was transformed into the Huh7 cells expressing HCV nonstructural proteins, and viral
replication was demonstrated in hygromycin resistant clones by detection of fluorescence. The viral
vector was then modified to encode toxins or cell death signaling mols., such as ricin A or interferon
regulating factor 1, and cell death was demonstrated in transformed clones. This invention is intended
to be used as pharmaceutical compd. in the prevention or treatment of viral infections from pos.
strand, single-stranded RNA viruses.
3- Antiviral agents that activate RNase L. Silverman, Robert. (The Cleveland Clinic Foundation,
USA). PCT Int. Appl. (2007), 65 pp. CODEN: PIXXD2 WO 2007127212 A2 20071108
Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC,
SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG. Designated States RW: AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, MT, NL, PT, SE, TR, BF, BJ, CF, CG, CI,
CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2007-US9959
20070425. Priority: US 2006-795069 20060425. CAN 147:496301 AN 2007:1278400 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Activators of RNase L, methods of using the same as antiviral agents, and pharmaceutical compns.
comprising the RNase L activators are disclosed. The activators of RNase L are not cytotoxic, they
77
inhibit smooth muscle cell proliferation in vitro, and therefore have utility in treating restenosis. They
can be also used to treat cancer. Thus, a 2-5A competition binding assay using surface plasmon
resonance on a Biacore model 3000TM was used to det. if an activator interacts with the 2-5A binding
domain of RNase L. The compd. C-5950331 competed with 2-5A for RNase L binding with the
binding const. of 18 μM. The compd. C-5950331 had low cytotoxicity in DU145 and HeLa cells and
showed antiviral activity against vaccinia virus (strain Western Reserve (WR)), a DNA virus in the
pox virus family.
4- Preparation of nitrogen-containing heterocycle derivatives as antiviral agents. Mjalli,
Adnan M.M.; Cooper, Jeremy T.; Arimilli, Murty N.; Andrews, Robert C.; Rothlein, Robert; Altel,
Taleb H. (Transtech Pharma, Inc., USA). U.S. Pat. Appl. Publ. (2007), 53 pp. CODEN:
USXXCO US 2007219239 A1 20070920 Patent written in English. Application: US 2007-
704763 20070209. Priority: US 2006-772309 20060210. CAN 147:385981 AN 2007:1054300
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Title compds. I [R1 = CN, CF3, OCF3, NO2, cycloalkyl, etc.; R2 = halo, NH2, CO2H, OH,
(cyclo)alkyl, (hetero)aryl, etc.; G1 and G2 independently = (un)substituted cycloalkyl, heterocyclyl,
aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl or fused heterocyclylheteroaryl; L1, L2 and L5 independently = direct bond,
(un)substituted alkylene, alkenylene or alkynylene; L3 and L4 independently = direct bond,
(un)substituted alkylene, alkenylene, alkynylene, arylene or heteroarylene; Y1 and Y2 independently =
direct bond, O, C(O), S, OC(O), SO, SO2, etc.; ring A = 5-membered satd. heterocyclyl; V and X
independently = C or N; W, Y or Z independently = O, S, NR5 or CR6; Q = (CR3R4)n, wherein R3-6
independently = H, (un)substituted (cyclo)alkyl, alkylene-cycloalkyl or aryl; CR3R4 = (un)substituted
5- to 7-membered (hetero)cyclyl; n = 0-1; m and p independently = 0-2], and their pharmaceutically
acceptable salts, solvates or prodrugs thereof, are prepd. and disclosed as antiviral agents. Thus, e.g.,
II was prepd. in 11 steps starting from 5-nitroisophthalic acid monomethyl ester and using [(R)-4-
fluorophenethyl]amine. Exemplar compds. of the invention were found to inhibit viral replication in
vaccinia viral assay with an EC50 of ≤ 100 μM, e.g., II showed EC50 value of ≤ 0.5 μM. As antiviral
agents, I should prove useful in the treatment of viral infections and may be administered to a subject
for antiviral therapy or prophylaxis.
5- Anesthetic compound-steroid combination antiviral treatment. Fabunan, Ruben G. (Fil-Am
Tech., Inc., USA). PCT Int. Appl. (2007), 16 pp. CODEN: PIXXD2 WO 2007084548 A2
20070726 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
78
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY,
MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG. Designated States
RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2007-
US1210 20070117. Priority: US 2006-759847 20060118. CAN 147:181517 AN 2007:817659
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Common colds, influenza, Dengue fever, mumps, measles, hepatitis, rabies, conjunctivitis,
chickenpox, herpes, and HIV infection are treated by i.m. injection of a mixt. comprising a first
ingredient selected from the group consisting of chloroprocaine, tetracaine, chlorotetracaine,
bromoprocaine, proparacaine, fluoroprocaine and benzocaine, and a second ingredient selected from
the group consisting of dexamethasone, flumethasone and betamethasone, or by i.m. injection of a
mixt. comprising a first ingredient selected from the group consisting of procaine, chloroprocaine,
tetracaine, chlorotetracaine, bromoprocaine, proparacaine, fluoroprocaine and benzocaine, and a
second ingredient selected from the group consisting of flumethasone and betamethasone. Compns. of
the invention are administered to prevent HIV from attaching to and penetrating host cells, to penetrate
sanctuary sites to inactivate HIV and to generate vaccines from inactivated HIV.
6- Preparation of antiviral azanucleoside derivatives as inhibitors RNA-dependent viral
polymerases. Chiacchio, Ugo; Mastino, Antonio; Merino, Pedro; Romeo, Giovanni. (Istituto di
Ricerche di Biologia Molecolare P. Angeletti S.p.A., Italy). PCT Int. Appl. (2007), 45pp.
CODEN: PIXXD2 WO 2007065883 A1 20070614 Designated States W: AE, AG, AL, AM, AT,
AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE,
EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG,
NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
TR, TT, TZ, UA, UG. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS,
IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent
written in English. Application: WO 2006-EP69288 20061204. Priority: IT 2005-611 20051206.
CAN 147:72983 AN 2007:643846 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
79
Abstract
Azanucleoside analogs I, wherein B is a heterocyclic base, or nucleosidic base; R1 is H, linear or
branched alkyl group, or (un)satd. cycloalkyl groups; R2 is amido, keto or thioketones, linear or
branched alkyl groups, or aryl or benzyl groups; R3 is H or a group convertible in vivo to phosphorous
contg. groups; R4 is H, linear or branched alkyl groups, (un)satd. alkyl groups, or (un)satd. acyl
groups are prepd. and have antiviral activity. Thus, II was prepd. and tested for its HCV-NS3 redn.
assay toxicity (IC50 was 4.8 μM). Further, I can be successfully employed in the treatment of viral
infections such as inhibitor of RNA-dependent RNA polymerases, or viruses from the Flaviviridae,
Orthomyxoviridae, Rheoviridae, Bunyaviridae, or Retroviridase families.
7- Five-membered iminocyclitol derivatives as selective and potent glycosidase inhibitors: new
structures for antivirals and osteoarthritis therapeutics. Liang, Pi-Hui; Lin, Yi-Ling; Wong,
Chi-Huey. (Academia Sinica, Taiwan). PCT Int. Appl. (2007), 33pp. CODEN: PIXXD2 WO
2007067515 A2 20070614 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT,
SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2006-US46348 20061205. Priority: US 2005-742406 20051205. CAN
147:46158 AN 2007:642739 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention discloses 5-membered iminocyclitol derivs. which were found to be a potent and
selective inhibitors of the glycoprotein processing α-and β-glucosidase and were further found to be
active antiviral agents against Japanese encephalitis virus, dengue virus serotype 2 (DEN-2), human
SARS coronavirus and human β-hexosaminidase, a new target for development of osteoarthritis
therapeutics. Prepn. of compds. of the invention is included.
8- TMAZ as an antiviral agent and use thereof. Lelas, Tihomir. (Ljubicic, Mijo, Germany;
Ivkovic, Slavko). PCT Int. Appl. (2007), 56pp. CODEN: PIXXD2 WO 2007054085 A2
20070518 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA,
MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU,
80
SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG,
CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in German. Application: WO 2006-
DE2008 20061110. Priority: DE 2005-102005054306 20051111. CAN 146:514706 AN
2007:538497 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention discloses antiviral pharmaceutical agents comprising esp. tribomechanically activated
zeolites and propolis and/or colostrum. The invention also discloses the use of these agents,
preferably for HIV and hepatitis infections.
9- Pyrazoline derivatives for treatment of viral infections. Ferguson, David M.; Goodell, John.
(Regents of the University of Minnesota, USA). PCT Int. Appl. (2007), 78pp. CODEN: PIXXD2
WO 2007038425 A2 20070405 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG,
BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD,
GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT,
SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2006-US37241 20060926. Priority: US 2005-721002 20050927. CAN
146:395241 AN 2007:384400 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention provides anti-viral compds. of formula (I) wherein R1-R3 and A have any of the values
defined herein. The invention also provides pharmaceutical compns. comprising such compds. as well
as methods for treating viral infections by administering such compds. to an animal. A prepd. triaryl
pyrazoline deriv. demonstrated significant antiviral activity against West Nile, dengue fever, yellow
fever, and western equine encephalitis viruses.
10- Pyrrolidine derivatives as immunomodulators and antiviral agents. Nash, Robert James;
Carroll, Miles William; Watson, Alison Ann; Fleet, George William John; Horne, Graeme. (MNL
Pharma Limited, UK). PCT Int. Appl. (2007), 72pp. CODEN: PIXXD2 WO 2007010266 A1
20070125 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HN, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC,
81
SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC. Designated States
RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-
GB2717 20060720. Priority: GB 2005-14865 20050720. CAN 146:177231 AN 2007:88241
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention discloses pyrrolidine compds. and their use in therapy and prophylaxis. In particular,
the invention discloses the use of various pyrrolidine compds. (including N-hydroxyethyl-DMDP and
certain analogs thereof) as immunomodulatory (immunostimulatory or immunosuppressive) drugs
and/or as antivirals (e.g. as glycovirs or alkovirs).
11- Preparation of 2,3,4,9-tetrahydro-1H-β -carbolines for treatment of dengue fever, yellow
fever, West Nile virus, and hepatitis C virus infection. Gudmundsson, Kristjan. (Smithkline
Beecham Corporation, USA). PCT Int. Appl. (2007), 53pp. CODEN: PIXXD2 WO
2007002051 A1 20070104 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU,
LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO,
RS, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT,
SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2006-US23928 20060619. Priority: US 2005-692810 20050622. CAN
146:100663 AN 2007:13571 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Title compds. I [wherein each R1 = halo, (halo)alkyl, alkenyl, etc.; p = 0-4; n = 0 or 1; X = C(O),
C(O)O, SO2, etc.; R2, R3 = (un)substituted (hetero)aryl or heterocyclyl] and pharmaceutically
acceptable salts, solvates, and physiol. functional derivs. thereof were prepd. for the treatment of
infection due to Flaviviridae, such as flaviviruses, pestiviruses, and hepaciviruses, particularly dengue
fever, yellow fever, West Nile virus, or HCV. Thus, cyclization of 5-bromotryptamine hydrochloride
with p-tolualdehyde in glacial acetic acid (80%) followed by treatment with benzyl chloroformate led
to II. This compd. showed anti-HCV activity with IC50 = 5 nM.
82
2006 – 14 patents
1- Preparation of nucleosides with non-natural bases as anti-viral agents. Storer, Richard;
Gosselin, Gilles; Griffon, Jean-Francois; Pierra, Claire. (Idenix (Cayman) Limited, Cayman I.; Centre
Nationale De La Recherche Scientifique). Can. Pat. Appl. (2006), 149pp. CODEN: CPXXEB
CA 2600359 A1 20060909 Patent written in English. Application: CA 2006-2600359 20060309.
Priority: US 2005-660117 20050309; WO 2006-IB2550 20060309. CAN 148:79268 AN
2007:1439303 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The prepn. nucleosides with non-natural bases I, wherein R1 is H or a halogen; R2 is an H or halogen,
but preferably F; R3 is (un)substituted amino; Q is independently N, CH or NH; and Z can be a
(un)substituted ribofuranosyl moiety, is presented. Further, Z can be modified as II, such that the Base
is described as I above; X is O, S, or NH; R is independently H, a substituted phosphate, phosphonate,
acyl, alkyl or amino acid group; A can be independently H, hydroxy, alkyl, alkenyl, halo, etc.; B is
independently H, alkyl, a halo substituted alkyl or a halogen. Thus, III was prepd. and tested treating a
host infected with flavivirus, pestivirus or hepacivirus (EC50 less than 15 μM). Subsequently, β-D
and β-L nucleosides of I are to be used as therapeutic prodrugs treating diseases related to viral
origins.
2- Acylguanidines as antiviral compounds and their preparation, pharmaceutical compositions
and use in the treatment of viral infections in mammals. Ewart, Gary Dinneen; Best, Wayne
Morris. (Biotron Limited, Australia). PCT Int. Appl. (2006), 49pp. CODEN: PIXXD2 WO
2006135978 A1 20061228 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT,
SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2006-AU880 20060623. Priority: AU 2005-903360 20050624. CAN 146:100349
AN 2006:1356781 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention relates to acylguanidine compds. of formula I and compns. having antiviral
activity. Compds. of formula I wherein R1 is (un)substituted (un)fused cinnamyl, (un)substituted
naphthyl, and (un)substituted phenyl; and their pharmaceutically acceptable salts thereof, are claimed.
The invention also relates to methods for the therapeutic or prophylactic treatment of viral infections
83
in mammals. Example compd. II was prepd. by olefination of 2,3-methylenedioxybenzaldehyde with
tri-Et phosphonoacetate; the resulting Et 2,3-methylenedioxycinnamate underwent hydrolysis to give
the corresponding cinnamic acid, which underwent amidation with guanidine to give compd. II. All
the invention compds. were evaluated for their antiviral activity, toxicity (TC50)and calcn. of the
antiviral index (AI). From the assay it was detd. that compd. II exhibited an IC50 value 1.1 μM, TC50
of > 100 μM, and AI > 100.
3- Preparation and antiviral activity of D-glucopyranose 1-[3,5-bis(1,1-dimethylethyl)-4-
hydroxybenzoate]. Vachy, Robert. (RDW Pharma, Fr.). Fr. Demande (2006), 16pp.
CODEN: FRXXBL FR 2887249 A1 20061222 Patent written in French. Application: FR 2005-
6304 20050621. Priority: . CAN 146:39014 AN 2006:1338924 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
FR 2887249 A1 20061222 FR 2005-6304 20050621
FR 2887249 B1 20070928
Priority Application
FR 2005-6304 20050621
Abstract
D-Glucopyranose 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate] was prepd. by esterification of D-
glucose with 3,5-di-tert-butyl-4-hydroxybenzoic acid and used as antiviral agent for treatment of
Herpes, AIDS, influenza of hepatitis B and C, dengue, and Ebola viruses. Title compd. was tested in
vitro as antiviral agent and showed better soly. of BHT and 3,5-di-tert-butyl-4-hydroxybenzoic acid.
4- Antisense antiviral oligonucletides targeting RNA stem-loop structure for treating infections
of ssRNA viruses. Iversen, Patrick L.; Stein, David A.; Weller, Dwight D. (Avi Biopharma, Inc.,
USA). U.S. Pat. Appl. Publ. (2006), 64pp., Cont.-in-part of U.S. Ser. No. 226,995. CODEN:
USXXCO US 2006269911 A1 20061130 Patent written in English. Application: US 2006-
432031 20060510. Priority: US 2004-611063 20040916; US 2005-226995 20050914. CAN
146:20246 AN 2006:1256345 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention provides antisense antiviral compds. and methods of their use and prodn. in inhibition
of growth of viruses of the Flaviviridae, Picomoviridae, Caliciviridae, Togaviridae, Arteriviridae,
84
Coronaviridae, Astroviridae and Hepeviridae families in the treatment of a viral infection. The
antisense antiviral compds. are substantially uncharged morpholino oligonucleotides having a
sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is
complementary to a region assocd. with stem-loop secondary structure within the 5'-terminal end 40
bases of the pos.-sense RNA strand of the virus. The antisense compds. are preferably
phosphorodiamidate-linked morpholino oligonucleotide (PMO) analogs. These PMOs may be
conjugates to Arg-rich peptides to enhance their cellular uptake. Thus, such antisense PMOs were
prepd. and shown to inhibit yellow fever virus, dengue virus, porcine reproductive and respiratory
syndrome virus, tick-borne encephalitis virus, and west nile virus in in vitro assays.
5- Preparation of carbazoles and related compounds for treatment of dengue fever, yellow fever,
west nile virus, and hepatitis C virus infection. Gudmundsson, Kristjan. (Smithkline Beecham
Corporation, USA). PCT Int. Appl. (2006), 59pp. CODEN: PIXXD2 WO 2006121467 A2
20061116 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU,
ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG,
MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK,
SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG,
CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2005-
US41091 20051114. Priority: US 2004-630166 20041122. CAN 145:489114 AN 2006:1207231
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Title compds. [I; n = 0-2; X = NH, O, S, SO, SO2; R, R1 = halo, haloalkyl, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, cyano, NO2,
N3, etc.; p, q = 0-5; A = aryl, heteroaryl], were prepd. for the treatment of infection due to flaviviruses,
pestiviruses, and hepaciviruses. Thus, 6-chloro-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine
(prepn. outlined) showed anti-HCV activity with IC50 = 5 nM.
6- Tetrahydrocarbazoles useful as inhibitors of hepatitis C and other viruses belonging to
Flaviviridae. Gudmundsson, Kristjan; Samano, Vicente. (Smithkline Beecham Corporation,
USA). PCT Int. Appl. (2006), 69pp. CODEN: PIXXD2 WO 2006118607 A2 20061109
Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK,
85
MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW: AT,
BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI,
CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2005-US41089
20051114. Priority: US 2004-629905 20041122. CAN 145:465666 AN 2006:1179153 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention relates to tetrahydrocarbazoles [shown as I; n = 0-2; t = 0 or 1; X = NH, O,
-R10-, -OR10-, -R10O-, -R10OR10-, NR10-, -R10N-, -R10NR10-, -R10S(O)m-, or R10S(O)mR10-;
Y = C(O), S(O)m; R and R1 independently = halo, haloalkyl, alk(en/yn)yl, cycloalkyl, cyano, nitro or
azido, et al.; m = 0-2; R10 = alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; p,
q = 0-5; A = (hetero)aryl; addnl. details including provisos are given in the claims; or salts, solvates
and physiol. functional derivs. thereof] that are useful in the treatment of viruses belonging to
Flaviviridae, including flaviviruses, pestiviruses, and hepaciviruses. The invention includes compds.
useful for the treatment or prophylaxis of dengue fever, yellow fever, West Nile virus, and HCV.
Although the methods of prepn. are not claimed, prepns. and/or characterization data for .apprx.70
examples of I are included. For example, 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine was
reacted with picolinoyl chloride to give II as a racemate in 63% yield, which was then sepd. into two
pure enantiomers by supercrit. fluid chromatog. IC50 values for inhibition of HCV activity are
tabulated for 6 examples of I, e.g. 6 nM for (R)-II.
7-Antiviral artificial CpG-containing single-stranded oligodeoxynucleotides in combination with
ribavirin. Wang, Li-Ying; Bao, Mu-Sheng; Yu, Yong-Li. (Changchun Huapu Biotechnology Co.,
Ltd., Peop. Rep. China). PCT Int. Appl. (2006), 74pp. CODEN: PIXXD2 WO 2006108358 A1
20061019 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU,
ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG,
MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK,
SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG,
CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in Chinese. Application: WO 2006-CN667
20060413. Priority: CN 2005-10064537 20050413. CAN 145:443761 AN 2006:1093278
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
86
Abstract
The present invention provides a compn. contg. ribavirin and artificial CpG single-stranded
oligodeoxynucleotides or a kit which can prevent or treat viral infection and infectious diseases caused
by virus, and use thereof. The invention also provides a method for preventing or treating viral
infection and infectious diseases caused by virus.
8- Sulfur oligonucleotides having antiviral activities. Vaillant, Andrew; Juteau, Jean-Marc.
(Replicor Inc., Can.). PCT Int. Appl. (2006), 51pp. CODEN: PIXXD2 WO 2006096995 A1
20060921 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU,
ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG,
MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK,
SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG,
CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-CA411
20060317. Priority: US 2005-662364 20050317. CAN 145:348566 AN 2006:978227 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Sulfur oligonucleotides having antiviral activities through a sequence-independent mode of action are
described, along with their use as broad spectrum therapeutic agents for treating viral infections. The
sulfur modification may be at any location (e.g., on the base moiety, sugar moiety, or internucleotidic
linkages) in order to confer the necessary chem. properties required for the sequence-independent
antiviral activity of oligonucleotides. The sulfur modification is necessary and can be addnl. to
another modification, like a phosphorothioate or phosphorodithioate modification. It is not necessary
for the oligonucleotide to be complementary to any viral sequence or to have a sequence-dependent
aptameric activity or to have a particular distribution of nucleotides in order to have activity. Different
lengths of random sequence sulfur-modified oligonucleotides have varying effect, with an optimal
length of 30-40 bases. Also described are methods for treatment of viral infections, cancers caused by
oncogene viruses, and other diseases whose etiol. is viral-based. Such method of treatment comprises
the administration of sulfur oligonucleotides to a human or an animal in an acceptable form alone or in
combination with another antiviral compd.
9- Preparation of quinazoline derivatives as antiviral agents. Cockerill, George Stuart; Flack,
Stephen, Sean; Mathews, Neil; Salter, James Iain. (Arrow Therapeutics Limited, UK). PCT Int.
Appl. (2006), 27pp. CODEN: PIXXD2 WO 2006079833 A1 20060803 Designated States W:
87
AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE,
DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM,
KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA,
NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW: AT, BE, CH, CY, DE, DK, ES,
FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE,
SN, TD, TG. Patent written in English. Application: WO 2006-GB294 20060130. Priority: GB
2005-1964 20050131; US 2005-649564 20050204; US 2005-668456 20050405. CAN 145:211057
AN 2006:765057 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Quinazoline derivs. [I; X = direct bond, LNR; R = H, C1-C4 alkyl; L = C1-C4 alkylene, C6-C10
arylene, or 5-to-10-membered heteroarylene; R1 = H, C6-C10 aryl, C1-C4 (hydroxy)alkyl; R2 = C6-
C10 aryl, C1-C4 (hydroxy)alkyl; R3 = C6-C10 (un)substituted aryl, C3-C6 (un)substituted
carbocyclyl, 5-to-10-membered (un)substituted heteroaryl, 5-to-10-membered (un)substituted
heterocyclyl; NR1R2 = 5-to-10-membered heterocyclyl, 5-to-10-membered heteroaryl; e.g., N-(4-
morpholinophenyl)-6-[4-(4-morpholinophenylamino)quinazolin-6-yl]quinazolin-4-amine], which are
active in inhibiting the replication of flaviviridae, are prepd.
10- Antiviral activity from medicinal mushrooms. Stamets, Paul. (USA). U.S. Pat. Appl. Publ.
(2006), 14pp., Cont.-in-part of U.S. Ser. No. 145,679. CODEN: USXXCO US 2006171958 A1
20060803 Patent written in English. Application: US 2006-386402 20060322. Priority: US 2004-
534776 20040106; US 2005-29861 20050104; US 2005-145679 20050606. CAN 145:195587
AN 2006:763418 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Compds. having unique antiviral properties are prepd. from medicinal mushroom mycelium, exts. and
derivs. The compns. are derived from Fomitopsis, Piptoporus, Ganoderma and blends of medicinal
mushroom species and are useful in preventing and treating viruses including Orthopox viruses,
influenza, avian influenza, Venezuelan Equine Encephalitis, yellow fever, West Nile, Dengue, New
World and Old World arenaviruses, hantavirus, Rift Valley fever, sandfly fever, hantavirus, SARS,
Rhinovirus and other viruses.
11- Antiviral drug combinations using a glycosylation modulator and a membrane fusion
inhibitor. Nash, Robert James; Slingsby, Jason H.; Carroll, Miles William. (MNL Pharma Limited,
UK). PCT Int. Appl. (2006), 85 pp. CODEN: PIXXD2 WO 2006077427 A2 20060727
Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
88
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK,
MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW: AT,
BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI,
CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-GB209
20060120. Priority: GB 2005-1352 20050121. CAN 145:180926 AN 2006:733122 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention discloses a combined prepn. comprising a glycosylation modulator and a membrane
fusion inhibitor for combined, simultaneous, or sequential use in the treatment of infections caused by
viruses bearing glycosylated envelope proteins.
12- Antiviral antisense oligonucleotides for treating ss(+)RNA viral infection. Iversen, Patrick
L.; Stein, David A. (USA). U.S. Pat. Appl. Publ. (2006), 62 pp. CODEN: USXXCO US
2006063150 A1 20060323 Patent written in English. Application: US 2005-226995 20050914.
Priority: US 2004-611063 20040916. CAN 144:306424 AN 2006:273262 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Abstract
The invention provides antisense antiviral compds. for inhibition of replication of Flaviviridae,
Picornoviridae, Caliciviridae, Togaviridae, Arteriviridae, Coronaviridae, Astroviridae and Hepeviridae.
The antisense antiviral compds. are substantially uncharged morpholino oligonucleotides having a
sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is
complementary to a region assocd. with stem-loop secondary structure within the 5'-terminal end 40
bases of the pos.-sense RNA strand of the virus. The antisense oligonucleotides may be conjugated to
an arginine-rich peptide to promoter uptake into infected host cells. Thus, a phosphorodiamidate-
linked morpholino oligonucleotide targeting the 5'-terminal of West Nile virus RNA conjugated to
(RAhxR)4AhxβAla (Ahx = 6-aminohexanoic acid; βAla = β-alanine) was shown to prolong survival
of mice infected with the virus.
13- Preparation of nucleoside-lipid conjugates as antiviral and antitumor agents. Ahmad,
Moghis U.; Ali, Shoukath M.; Khan, Abdul R.; Ahmad, Imran. (Neopharm, Inc., USA). PCT Int.
Appl. (2006), 72 pp. CODEN: PIXXD2 WO 2006029081 A2 20060316 Designated States W:
AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE,
DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM,
89
KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ,
UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES,
FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE,
SN, TD, TG. Patent written in English. Application: WO 2005-US31543 20050902. Priority: US
2004-606610 20040902. CAN 144:292980 AN 2006:235096 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
The invention provides methods for synthesizing nucleoside-lipid conjugates I, wherein Y1 and Y2 are
the same or different and are -O-C(O)-, -O-, -S-, -NH-C(O)- or the like; R1 and R2 are independently
H, satd. alkyl group and unsatd. alkyl group; X is H, alkyl group and a cation; R3 is a nucleoside
selected from a group consisting of cytosine, guanine, adenine, thymine, uracil, inosine, xanthine and
hypoxanthine; R4 and R5 are independently hydrogen, hydroxy, halo group, nitro, alkyl group,
substituted alkyl and alkoxy group; R6 is hydrogen, hydroxy group, azido group, amino group, alkyl
group, halo group and substituted amino; five membered cyclic sugar is selected from a group
consisting of ribofuranose, arabinofuranose, deoxyribofuranose and xylofuranose having varying fatty
acid and alkyl chain lengths with or without unsatn. and their use in the treatment of cancer and viral
diseases. More particularly, the invention provides methods for prepg. gemcitabine-cardiolipin
conjugates, and analogs thereof, cytarabine-cardiolipin conjugates, and analogs thereof. Addnl., the
methods of the invention comprise administering a compd. of invention as prodrug or a
pharmaceutical prepn. to combat mammalian diseases, preferably cancer, viral infections and bone
disorders. The cancer is selected from a group consisting of cancers of the head, neck, brain, blood,
breast, lung, pancreas, bone, spleen, bladder, prostate, testes, colon, kidney ovary, and skin. The viral
disease is selected from a group consisting of HIV, Herpes simplex viruses, human Herpes virus 6,
human Herpes virus 7, human Herpes virus 8, Ebola virus, Influenza virus, Tuberculosis, Hepatitis A,
Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Parainfluenza virus, Respiratory syncytial virus,
Cholera, pneumonia, SARS virus, West Nile virus, Respiratory syncytial virus, Dengue virus, Corona
viruses, Vaccinia virus, Cytomegalovirus, human Rhinovirus, Papilloma virus, and Human
Herpesvirus 4.
The bone disorder is selected from a group consisting of osteoporosis, Paget's disease, metastatic bone
cancers, hyperparathyroidism, rheumatoid arthritis, Gaucher's disease. Thus, 5'-O-succinyl[2-O-1,3-
bis(1,2-O-dimyristoyl-sn-glycero)-3-phosphorylglycerol dimethylester] gemcitabine was prepd. and
tested in-vitro and in mice as antiviral and antitumor agent. The toxicity of gemcitabine-cardiolipin
conjugate at 18 μmol/kg after 6 daily treatments and the body wt. loss on day 7 was significantly less
90
compared to gemcitabine. When mice were treated with gemcitabine-cardiolipin conjugate at 18
μmol/kg for 5 days, the max. body wt. loss was only 3 % compare to 22 % for gemcitabine.
14- Improved synthesis of sodium pentaborate pentahydrate (NaB5O8.5H2O) for use in
antibacterial and antiviral compositions. Galvan Perez, Juan Pablo. (Mex.). PCT Int. Appl.
(2006), 81 pp. CODEN: PIXXD2 WO 2006025724 A1 20060309 Designated States W: AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK,
DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO,
NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA,
UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI,
FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN,
TD, TG. Patent written in Spanish. Application: WO 2005-MX79 20050902. Priority: MX 2004-
8485 20040902. CAN 144:265950 AN 2006:213041 CAPLUS (Copyright (C) 2010 ACS on
SciFinder (R))
Abstract
The invention relates to an improved method for the synthesis of sodium pentaborate pentahydrate
(NaB5O8.5H2O), which consists in reacting disodium tetraborate decahydrate (borax) with orthoboric
acid (boric acid). The method is performed over a period of no more than five days and does not
require the use of fungal strains. Pharmaceutical compns. contg. NaB5O8.5H2O are used to boost the
immune system against ailments caused by bacteria and viruses. Thus, NaB5O8.5H2O was effective
against 14 bacterial species in vitro at 400 mg/mL.
91
2005 – 14 patents
1- Potent and selective inhibition of viral replication by aurintricarboxylic acid. He, Runtao;
Andonov, Anton; Cao, Jingxin; Drebot, Mike; Li, Xueguang. (Canada, Minister of Health, Can.).
PCT Int. Appl. (2005), 64 pp. CODEN: PIXXD2 WO 2005123965 A1 20051229 Designated
States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA,
NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML,
MR, NE, SN, TD, TG. Patent written in English. Application: WO 2005-CA924 20050615.
Priority: US 2004-579247 20040615; US 2004-608862 20040913. CAN 144:81142 AN
2005:1354624 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Described herein is a method of inhibiting replication of an organism which has an essential enzyme
which includes a binding groove that is bound by ATA comprising administering to a patient in need of
such treatment an effective amt. of aurintricarboxylic acid (ATA). In this study, the inventors analyzed
the effect of aurintricarboxylic acid (ATA) on SARS-CoV replication in cell culture, and found that
ATA could drastically inhibit SARS-CoV replication, with viral prodn. being more than 1000 fold than
that in the untreated control. As can be seen in Figure 4, a putative 3D structure of SARS RNAP and
ATA (using an ATA ligand model) shows the template binding groove of RNAP which is also bound
by ATA. That is, ATA binding at this groove prevents template binding and therefore viral replication
by RNAP. Furthermore, as can be seen from the sequence comparison shown in Figure 5, enzymes
from other organisms known to be inhibited by ATA have similar grooves. In addn., the inhibitory
effect of aurintricarboxylic acid (ATA) on vaccinia virus replication in tissue culture is described
herein. Concns. of ATA in the range of 400 μg/mL decreased viral replication as much as 250,000 fold
as compared to controls. A block in replication was evident at drug concns. as low as 25 pg/mL.
Inhibition of the viral phosphatase, H1L, which is essential for virus replication, was found to be one
mechanism through which ATA exerts its antiviral effect. Western blotting also revealed that the ERK
signaling cascade was down-regulated in cells treated with ATA. The activity of the ERK signaling
cascade has previously been implicated in the vaccinia virus lifecycle. As discussed below, ATA is an
effective antiviral for coronaviruses, for example, SARS-CoV, West Nile Virus, Norwalk, Dengue and
Japanese Encephalitis virus.
92
2- Interferon combination therapy. Seiwert, Scott D.; Blatt, Lawrence M.; Tan, Hua; Derrick,
Jena Rey; Hong, Jin; Radhakrishnan, Ramachandran. (Intermune, Inc., USA). PCT Int. Appl.
(2005), 134 pp. CODEN: PIXXD2 WO 2005123113 A2 20051229 Designated States W: AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK,
DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO,
NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA,
UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI,
FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN,
TD, TG. Patent written in English. Application: WO 2005-US21050 20050614. Priority: US
2004-579625 20040614. CAN 144:86581 AN 2005:1350327 CAPLUS (Copyright (C) 2010
ACS on SciFinder (R))
Abstract
The authors disclose combination therapy comprising interferon-α (IFN-α) and IFN-γ. The
combination therapy is useful for treating viral infections, fibrotic disorders, and proliferative diseases.
3- Preparation of morpholinylanilino quinazoline derivatives for use as antiviral agents.
Spencer, Keith; Dennison, Helena; Matthews, Neil; Barnes, Michael; Chana, Surinder. (Arrow
Therapeutics Limited, UK). PCT Int. Appl. (2005), 55 pp. CODEN: PIXXD2 WO 2005105761
A1 20051110 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,
CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK,
MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM,
SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW:
AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG,
CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2005-
GB1598 20050428. Priority: GB 2004-9494 20040428; GB 2004-25268 20041116. CAN
143:460186 AN 2005:1193587 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Title compds. I [wherein R1 - R4 = H, alkyl, haloalkyl, etc., and pharmaceutically acceptable salts
thereof] were prepd. as antiviral agents. For instance, thermal cyclization of 5-bromo-2-aminobenzoic
acid with formamide followed by chlorination with thionyl chloride gave crude 6-bromo-4-
chloroquinazoline, which was condensed with 4-morpholinoaniline in refluxing acetonitrile to afford
II. This compd. showed activity in reducing the replicon level with IC50 of < 5 μM and in reducing
93
the cell area with TD50 of >25 μM in the cell culture assay using HCV replicon cells Huh 9B.
Therefore, I and their pharmaceutical compns. are effective in treating or preventing flaviviridae
infections.
4- Preparation of novel sugar chain-supported carbosilane dendrimer. Terunuma, Daiyo;
Hatano, Ken; Suzuki, Yasuo; Jwa, Ilpall. (Saitama University, Japan; Shizuoka Prefecture; Matsuoka,
Koji). PCT Int. Appl. (2005), 57 pp. CODEN: PIXXD2 WO 2005103064 A1 20051103
Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
IN, IS, KE, KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN,
TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY,
DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA,
ML, MR, NE, SN, TD, TG. Patent written in Japanese. Application: WO 2005-JP7755 20050419.
Priority: JP 2004-124757 20040420. CAN 143:440686 AN 2005:1171104 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Abstract
Sugar chain (oligosaccharide)-supported-carbosilane dendrimers represented by the following general
formula (R1)mSi{-R2-Si(R6)l[R3-Si(R7)k(R4-S-R5-A)3-k]3-l}n, the following general formula
(R1)mSi[-R2-Si(R6)l(R4-S-R5-A)3-l], or the following general formula (R1)mSi(R4-S-R5-A)n (R1,
R6, R7 = C1-6 alkyl, Ph, vinyl, allyl; R2, R3, R4, R5 = C1-6 alkylene, phenylene, alkenylene; A =
paraglobosyl (Q) (R = H), α-mannopyranosyl, group derived by removing H from 1-OH group of
mannooligosaccharide contg. 2-8 mannose; m = an integer of 0-3, n = an integer of 1-4, and m+n=4; k,
l = 1, 0-2) are prepd. A Dengue fever virus infection inhibitor, an antiviral agent, and a target
substance for the screening of anti-HIV agents contg. the sugar chain-supported-carbosilane dendrimer
as an active ingredient are also disclosed. Thus, 27.9 mg carbosilane dendrimer of formula
Me2Si[(CH2)3Si(CH2CH2Br)3]2 and 345.3 mg paragloboside Q(CH2)5SAc (R = Ac) were dissolved
in 0.4 mL dry DMF, treated with dry MeOH, thoroughly stirred, treated dropwise with 0.280 mL 1 M
NaOMe/MeOH, stirred at room temp. for 11 h, neutralized by adding 0.2 mL AcOH, concd., treated
with dry pyridine and 2.5 mL Ac2O, stirred at 30ϒ for 4 h to give 44% (110.0 mg)
[[Q(CH2)5S(CH2)3]3SiCH2CH2]2SiMe2 (R = Ac) (I). I (69.6 mg) was dissolved in 1.0 mL dry
MeOH, treated with 3.5 mg NaOMe, stirred at room temp. for 30 min, treated with 5.0 mL 0.1M aq.
NaOH soln., stirred for 5 h, further treated with 5.0 mL 0.1M aq. NaOH soln., stirred for 21 h,
neutralized with Amberlite IR120B, concd., and purified by gel permeation chromatog. (GPC) to give
[[Q(CH2)5S(CH2)3]3SiCH2CH2]2SiMe2 (R = H) (II). II in vitro lowered the infection rate of
94
BHK21 cells by Dengue fever virus to 47.16 and 53.95% at 0.5 and 1 mM, resp., from 100% for
control cells vs. 2.26% for heparin 100 μg/mL.
5- Method for discovery and development of broad-spectrum antiviral drugs. Buscher,
Benjamin A.; Dyall, Julie; Jockel-Balsarotti, Jennifer I.; O'Guin, Andrew K.; Olivo, Paul D.; Roth,
Robert M.; Zhou, Yi. (USA). U.S. Pat. Appl. Publ. (2005), 36 pp. CODEN: USXXCO US
2005164167 A1 20050728 Patent written in English. Application: US 2004-766226 20040128.
Priority: . CAN 143:146652 AN 2005:672730 CAPLUS (Copyright (C) 2010 ACS on SciFinder
(R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20050164167 A1 20050728 US 2004-766226 20040128
Priority Application
US 2004-766226 20040128
Abstract
The invention discloses a method for identifying a broad-spectrum antiviral lead compd. Also
disclosed are methods for marketing and delivering a broad-spectrum antiviral compd. and methods
for treating patients with antiviral infections with a broad-spectrum antiviral drug.
6- Method of regulating phosphorylation of sr protein and antiviral agents comprising sr protein
activity regulator as the active ingredient. Hagiwara, Masatoshi; Fukuhara, Takeshi; Suzuki,
Masaaki; Hosoya, Takamitsu. (Japan). PCT Int. Appl. (2005), 122 pp. CODEN: PIXXD2 WO
2005063293 A1 20050714 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK,
SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States
RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in Japanese. Application: WO 2004-
JP19393 20041224. Priority: JP 2003-435085 20031226. CAN 143:126753 AN 2005:612118
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
It is intended to provide: (1) antiviral agents lowering or inhibiting the activity of an SR protein, more
specifically speaking, (i) an antiviral agent promoting the dephosphorylation of an SR protein and (ii)
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an antiviral agent inhibiting a protein phosphorylating an SR protein; (2) an antiviral agent inhibiting
the expression of an SR protein; and (3) an antiviral agent activating a protein having an opposite
function to an SR protein. It is also intended to provide compds. which inhibit SRPK phosphorylating
an SR protein. These compds. inhibit the activity of the SR protein and show an antiviral effect.
Thus, antiviral agents which are efficacious against a novel virus and widely applicable and show a
highly sustained effect are provided to cope with the occurrence of various novel viruses.
7- A West Nile virus (WNV) reverse genetics dual-reporter system for high throughput cell-based
screening and identifying antivirals and vaccines against flaviviral infections. Shi, Pei-Yong;
Lo, Michael; Tilgner, Mark. (Health Research, Inc., USA). U.S. Pat. Appl. Publ. (2005), 81 pp.
CODEN: USXXCO US 2005058987 A1 20050317 Patent written in English. Application: US
2003-706892 20031113. Priority: US 2002-427117 20021118. CAN 142:309857 AN
2005:238534 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Patent Family Information
Patent No. Kind Date Application No. Date
US 20050058987 A1 20050317 US 2003-706892 20031113
US 7355033 B2 20080408
Priority Application
US 2002-427117P P 20021118
Abstract
The invention relates to compns. and methods for the identifying novel chemotherapeutics and
vaccines effective against flaviviral infections, such as, West Nile virus (WNV) and other emerging
flaviviruses, such as, Japanese encephalitis virus (JEV), St. Louis encephalitis virus (SLEV),
Alkhurma virus (AV), Kadam virus (KV), Jugra virus (JV), Cacipacore virus (CV), Yaounde virus
(YV), Tick-borne encephalitis virus (TBEV), Dengue viruses (DENV-1, DENV-2, DENV-3, DENV-
4), Yellow fever virus (YFV) and Murray Valley encephalitis virus (MVEV). The instant invention
provides stable and novel lineage I WNV reverse genetics systems, and methods for making the
reverse genetics systems , specifically, a fully-infectious WNV cDNA or replicon system engineered
with one or more nucleotide sequences each encoding a reporter gene to be used in high throughput
cell-based screening assays for the identification of antiflaviviral chemotherapeutics and/or vaccines
effective to treat and/or immunize against infections by WNV and other flaviviruses. The present
invention further provides methods of high throughput screening of antiflaviviral compds. or improved
derivs. thereof using novel lineage I WNV reverse genetics systems and/or cell lines stably contg. the
96
reverse genetics systems. Also, the invention provides novel pharmaceutical compns. comprising an
attenuated lineage I WNV that is less virulent but similarly immunogenic as the parent WNV and is
capable of providing a protective immune response in a host.
8- Antimetabolite antiviral dosing regimen for hepatitis C virus or flaviviridae therapy.
Stuyver, Lieven J. (Belg.). U.S. Pat. Appl. Publ. (2005), 23 pp. CODEN: USXXCO US
2005049220 A1 20050303 Patent written in English. Application: US 2004-921052 20040818.
Priority: US 2003-496202 20030818. CAN 142:254563 AN 2005:185375 CAPLUS (Copyright
(C) 2010 ACS on SciFinder (R))
Abstract
An anti-hepatitis C agent which is an antimetabolite to the host and cannot be administered on a daily
or chronic basis as is usual in antiviral therapy (referred to below as an "anti-HCV antimetabolite"),
can be administered using a traditional anticancer dosing regimen (for example via i.v. or parenteral
injection), over a period of 1-7 days followed by cessation of therapy until rebound of the viral load is
noted. This dosing regimen runs counter to conventional antiviral experience, wherein effective
agents are usually administered over at least fourteen days of sustained therapy, and typically on an
indefinite daily basis.
9- Virally encoded RNAs as substrates, inhibitors, and delivery vehicles for RNAi and uses for
antiviral therapy. Kowalik, Timothy F.; Stadler, Bradford M. (University of Massachusetts,
USA). PCT Int. Appl. (2005), 123 pp. CODEN: PIXXD2 WO 2005019433 A2 20050303
Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR,
NE, SN, TD, TG. Patent written in English. Application: WO 2004-US27436 20040823. Priority:
US 2003-497156 20030822; US 2004-566114 20040427. CAN 142:273968 AN 2005:182814
CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention provides methods for identifying druggable targets in assays that feature
compns., cells and/or organisms having structured viral non-coding RNAs (svRNAs) and an RNA
interference (RNAi) pathway. Methods for identifying antiviral agents and creating vaccines are also
featured. The invention further provides methods for inhibiting RNAi involving svRNAs or inhibitory
97
derivs. thereof. The invention also provides compns. for delivering siRNA and miRNA mols. derived
from svRNA loci and methods of use thereof. Antiviral vaccine comprising vectors encoding siRNA
or miRNA from VA RNA locus are also featured.
10- The artificial CpG single strand deoxidation oligonucleotide and its antiviral uses. Yu,
Yongli; Wang, Liying. (Changchun Huapu Biotechnology Co., Ltd., Peop. Rep. China). PCT Int.
Appl. (2005), 22 pp. CODEN: PIXXD2 WO 2005014611 A1 20050217 Designated States W:
AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE,
DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB,
GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG.
Patent written in Chinese. Application: WO 2004-CN863 20040726. Priority: CN 2003-146157
20030725; CN 2003-156224 20030905. CAN 142:212308 AN 2005:141083 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The present invention disclosed a set of artificial ODNs which contain one or more CpG(s), the said
ODNs can stimulate human PBMC to produce antiviral substances. These antiviral substances make
cell avoid of the attack from virus, the influenza virus and the single strand plus RNA virus are
preferred, such as hepatitis C virus, dengue virus and Japanese encephalitis virus. Moreover, the
antiviral uses of artificial CpG ODNs and its uses for treating and preventing viral infection are also
provided.
11- Aggregation-free cysteine substitution derivatives of interleukins 28 and 29 retaining
biological activity and their preparation and therapeutic use. Brady, Lowell J.; Klucher, Kevin
M.; Chan, Chung; Dong, Dennis L.; Liu, Hong Y.; Sheppard, Paul O.; Bukowski, Thomas R.
(Zymogenetics, Inc., USA). U.S. Pat. Appl. Publ. (2005), 149 pp. CODEN: USXXCO US
2005037012 A1 20050217 Patent written in English. Application: US 2004-914772 20040809.
Priority: US 2004-559142 20040402; US 2004-551841 20040310; US 2003-493194 20030807.
CAN 142:238656 AN 2005:140553 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Derivs. of interleukins 28 (28A, 28B) and 29 in which a cysteine residue is substituted and which
retain receptor binding and biol. activity are described. The native forms of these interleukins have an
odd no. of cysteines and tend to form intermol. disulfide bonds during purifn. Substitution derivs. do
98
not crosslink and can be purified as monomers. These variants have antiviral activity and may be
useful in the treatment of infection. Manuf. of the variants as inclusion bodies in Escherichia coli
expression hosts using codon-optimized synthetic genes is demonstrated. Biol. activity was tested
using cultured medium from HEK cells showing transient expression of the gene. The conditioned
medium effectively inhibited the cytopathic effect of encephalomyocarditis virus against HeLa cells.
Anal. of gene expression showed that these variants induced the normal interferon response pathway.
12- Sense antiviral oligonucleotide analogs and method for treating ssRNA viral infection.
Iversen, Patrick L. (Avi Biopharma, Inc., USA). PCT Int. Appl. (2005), 81 pp. CODEN:
PIXXD2 WO 2005013905 A2 20050217 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA,
BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC,
SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW.
Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE,
TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 2004-US25401 20040806. Priority: US 2003-493990 20030807. CAN
142:233275 AN 2005:136499 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The invention provides sense antiviral compds. and methods of their use in inhibition of growth of
virus of the Flaviviridae, Picornoviridae, Caliciviridae, Togaviridae, Coronaviridae families and
hepatitis E virus in the treatment of a viral infection. The sense antiviral compds. are substantially
uncharged morpholino oligonucleotides having a sequence of (12-40) subunits, including at least (12)
subunits having a targeting sequence that is complementary to a region assocd. with stem-loop
secondary structure within the 3'-terminal end (40) bases of the neg.-sense RNA strand of the virus.
13- Preparation of modified fluorinated (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleoside analogs
as antiviral agents. Clark, Jeremy. (Pharmasset, Ltd., Barbados). PCT Int. Appl. (2005), 228
pp. CODEN: PIXXD2 WO 2005003147 A2 20050113 Designated States W: AE, AG, AL, AM, AT,
AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE,
EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT,
RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA,
ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
99
Application: WO 2004-US12472 20040421. Priority: US 2003-474368 20030530. CAN
142:94074 AN 2005:34765 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Abstract
The disclosed invention provides nucleoside analogs I, wherein B is purine and pyrimidine
nucleobase; X is O, S, CH2, Se, NH, N-alkyl, CHW, C(W)2; W is F, Cl, Br, iodo; R1 is H, phosphate,
H-phosphonate, acyl, Ph, alkyl, carboxyalkylamino, sulfonate ester, peptide, amino acid, sugar reside;
R2 and R2' are independently H, alkyl, alkenyl, alkynyl, vunyl, N3, CN, halogen, NO2, ester, alkoxy,
thioalkyl, sulfoxide, sulfonyl; R6 is alkyl, CN, Me, OMe, OEt, CH2OH, CH2F, N3, CHCN, CH2N3,
CH2NH2, CH2NHMe, CH2NMe2, alkylne; and methods of treating a Flaviviridae infection,
including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host,
including animals, and esp. human, using a (2'R)-2'-deoxy-2'-fluoro-2'-C-Me nucleosides, or a
pharmaceutically acceptable salt or prodrug thereof. Thus, (2'R)-2'-deoxy-2'-fluoro-2'-C-
methylcytidine was prepd. and tested as antiviral agent. The effects the nucleoside analogs tested on
human bone marrow cells are reported. (2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine shows activity
against Rhinovirus, West Nile virus, Yellow Fever virus, and Dengue virus. Cytotoxicity and effect of
nucleoside analogs on human bone marrow cells are reported.
14- Motifs of dengue virus envelope protein E of as a novel druggable region for antivirals.
Modis, Yorgo; Harrison, Stephen. (Children's Medical Center Corporation, USA). PCT Int. Appl.
(2005), 123 pp. CODEN: PIXXD2 WO 2005002501 A2 20050113 Designated States W: AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK,
DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR,
KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM,
PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent
written in English. Application: WO 2004-US12433 20040422. Priority: US 2003-464873
20030422; US 2003-505654 20030924. CAN 142:130691 AN 2005:29156 CAPLUS
(Copyright (C) 2010 ACS on SciFinder (R))
Abstract
Motifs of the dengue virus envelope glycoprotein E that may be used as drug targets are identified.
These motifs may be found in other class II viral envelope proteins E and so may form a general target
for virucides. The present invention further relates to methods of using the druggable regions to
screen potential candidate therapeutics for diseases caused by viruses having class II E proteins, e.g.
viral fusion inhibitors. The primary druggable target is the K1 hairpin loop involved in
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oligomerization of the E protein. Structures of the precursor and sol. forms of the protein were detd.
by X-ray crystallog. Comparison of the structures identified conformational changes and key
structural motifs involved in the oligomerization of the protein in fusion of the virus to the cell
membrane. A hydrophobic ligand-binding pocket was identified in the K1 loop of the protein. This
loop plays an important role in oligomerization and undergoes conformational changes during
formation of the trimer. Peptides derived from the stem region involved in loop formation bound with
fairly high affinity and specificity to the protein.
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