from demons to darlings: drugs from venoms
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Drugs from venoms was the theme ofa recent conference held on HeronIsland, Queensland, Australia (1621August 1998). Unlikely as this premisemight seem, there are some importantexamples of toxins or venom compo-nents being developed for pharmaceuti-cal use. The arrow poison tubocurarinehas been used in anaesthetic practice asa muscle relaxant for over 40 years, andmost modern muscle relaxants were de-signed with an understanding of thestructures of the curare alkaloids.Captopril, the first angiotensin convert-ing enzyme (ACE) inhibitor in clinicaluse, was developed as an analogue ofthe bradykinin potentiating peptidesfrom the venom of the Brazilian snakeBothrops jararaca, and even one of themost lethal toxins known, botulinumtoxin, has found a use in treating un-controllable muscle spasms.
The main themes explored duringthe conference were the benefits gainedfrom the exquisite selectivity of toxins,the structure-based design of newagents from an understanding of theSAR of toxins, and the use of toxins astools to probe potential therapeutic tar-gets at the molecular and functionallevels.
From fish killer to pain killerGeorge Miljanich (Neurex Corporation,California, USA) described progresswith the development of the calciumchannel blocker v-conotoxin MVIIA(SNX-111, ziconotide) as an agent fortreating intractable pain. This particularconotoxin, from the marine snail Conusmagus, is highly specific for N-typeCa21 channels, and it has been demon-strated that such channels are the majorcontributor to the calcium current in-volved in the release of neurotransmit-ters from nociceptive neurones in thespinal cord. Other reflexes appear to in-
volve transmitter release triggered byactivation of P/Q channels, and theyare not affected by ziconotide. Miljanichdescribed the clinical trials involvingthe intrathecal administration of ziconotide to patients with intractableneuropathic or cancer-related pain. Theoutcomes of Phase II trials were im-pressive, and results from two extensivePhase III studies are currently beinganalysed. Neurex plan to request FDAapproval soon for what will be anotherclear example of going from venom todrug.
Ziconotide is v-conotoxin MVIIA,which is just one of dozens of activepeptides that have been isolated fromConus venoms. The development ofthis aspect of venom research was out-lined by the principal pioneer in thearea, Baldomero Olivera (University ofUtah, Salt Lake City, UT, USA). He em-phasized how the conotoxins actedsynergistically in nature by havinggroups of toxins that acted on differ-ent functional components. At the neuromuscular junction, for example,v-conotoxins block Ca21 channels andreduce acetylcholine release, a-cono-toxins block acetylcholine receptors,and m-conotoxins block Na1 channels,especially preventing conduction ofmuscle action potentials. Olivera de-scribed recent work that is exploringthe potential of conantokins, whichblock NMDA receptors, in treatingepilepsy. So far, the development ofdrugs acting on NMDA receptors hasbeen disappointing, principally becauseof side effects. The conantokins arehighly selective for one subtype ofNMDA receptor, and it is hoped thatthis selectivity will translate into a use-ful therapeutic ratio.
With ~500 species of cone snails and~100 different peptides in each venom,this source must be expected to provide
additional toxins with the potential tobe developed into therapeutic agents.
Molecular scaffolds and structure-based drug designThe advent of high-field NMR spec-troscopy has enabled the three-dimen-sional structures of small peptides,such as the conotoxins, to be deter-mined relatively easily. Several speak-ers from Australia [Ray Norton andPaul Pallaghy, Biomolecular ResearchInstitute, Melbourne; Glenn King,Sydney University; Kathy Nielsen andJohn Gehrmann, Centre for DrugDesign and Development (CDDD),Brisbane] provided new informationabout structures of a- and v-conotox-ins and spider toxins. However, nomatter how good the resolution of thestructure, there can always be questionsabout conformational changes of thetoxin under physiological conditionsand on binding to the target. Some ofthe pitfalls of relying on NMR-derivedstructures were shown by MichaelRafferty (Parke-Davis, Ann Arbor, MI,USA). Using a benzodiazepine nucleusas a template, functional side chainswere added to mimic the predictedgeometry of the active residues of v-conotoxin MVIIA in attempts to findlow molecular weight analogues of thisCa21 channel blocker. The lack of suc-cess was subsequently ascribed to aconformational change in the toxin atphysiological pH. By contrast, a moreconventional high-throughput screeningapproach has provided lead com-pounds of low molecular weight.
A different approach to structure-based drug design was described byAndr Mnez (CEN Saclay, France). Hisgroup has successfully transferred func-tions of large proteins (such as metalbinding properties) to the much smallerframework typical of scorpion toxins
DDT Vol. 3, No. 12 December 1998 1359-6446/98/$ see front matter Elsevier Science. All rights reserved. PII: S1359-6446(98)01269-0 531
From demons to darlings:drugs from venoms
like charybdotoxin. The ability to mimicthe CD4 binding activity of gp120 in arelatively small peptide is impressive,and there may be some therapeutic po-tential in AIDS.
Toxins to probe therapeutic targetsToxins can be very useful as probes ofpotential therapeutic targets. They canbe used at the molecular level to revealdifferences between different subtypesof receptors or ion channels. This ap-proach was demonstrated on actions ofbrevetoxins and ciguatoxins on differenttypes of Na1 channels by presentationsby Richard Lewis (CDDD) and DavidAdams (University of Queensland,Brisbane, Australia). As well as provid-ing a better understanding of the prop-erties of tetrodotoxin-sensitive and -resistant Na1 channels, this work ex-plores the therapeutic potential of
agents that might act selectively on dif-ferent types of Na1 channels.
The ability of dendrotoxins frommamba snake venoms to distinguishdifferent subtypes within the Kv1 familyof K1 channels was used in a study by Alan Harvey and colleagues(Strathclyde University, Glasgow, UK)aimed at localizing different K1 chan-nels in the brain and looking for se-lective changes with ageing and inAlzheimer s disease. Use of the toxinsrevealed changes in subunit expressionin different conditions, leading tospeculation that there may be scope fortherapeutic intervention to improvecognitive function by targeting particu-lar subtypes within the Kv1 family ofK1 channels.
Future prospectsThe conference highlighted the rapidprogress being made in understanding
the structure and the pharmacologicaleffects of some known toxins. Manycontributions indicated the scope forfinding additional toxins with novelstructures and potentially useful activ-ity. However, the conference also em-phasized the considerable amount ofwork and the long time required to gofrom venom to drug. There is hope thatziconotide will be rapidly approved fortherapeutic use so that it will act as acatalyst for other projects in the area ofvenoms to drugs.
ACKNOWLEDGEMENTI thank Glenn King for providing thetitle of this article.
Alan HarveyStrathclyde Institute for Drug
ResearchUniversity of Strathclyde
Glasgow, UK G1 1XWe-mail: firstname.lastname@example.org
532 1359-6446/98/$ see front matter Elsevier Science. All rights reserved. PII: S1359-6446(98)01271-9 DDT Vol. 3, No. 12 December 1998
Inflammation of the lower airways iscentral to the pathophysiology of sev-eral severe lung diseases, in particularasthma and chronic obstructive pul-monary disease (COPD). The first meet-ing, held last year, on ConqueringAirway Inflammation in the 21stCentury focused upon airway inflam-mation, asthma and current therapy (b2-adrenoceptor agonists, glucocor-ticosteroids and theophylline), and in-troduced several new therapeutic tar-gets and anti-inflammatory molecules[Rogers, D.F. and Giembycz, M.A.(1998) Trends Pharmacol. Sci. 19,160164]. This years meeting, held atthe National Heart & Lung Institute(London, UK) on the 1416 September1998, extended discussion of inflam-mation to airways remodelling, and hadan increased emphasis on new targetsand molecules.
In several instances, pharmaceuticalmoieties, which last year had demon-
strated encouraging effects in preclini-cal evaluation, had now entered clinicaltrial. It was interesting to note that air-ways remodelling, although critical todevelopment of the irreversible com-ponent of impaired lung function inasthma and COPD, was not an end-point target for evaluation of drug effi-cacy. This is understandable, as remod-elling is not an easy parameter toquantify. However, inhibition and/or re-versal of airways remodelling may af-fect the overall value of any therapy forasthma and COPD. The following ac-count focuses upon the newer targetsand molecules discussed at the meet-ing, in particular where chemical struc-tures and clinical data were presented.
Phosphodiesterase inhibitorsElevation of cyclic AMP, either by b2-adrenoceptor agonists or as a result ofone of the possible mechanisms of ac-tion of theophylline, is a central thera-
peutic recommendation in guidelineson the management of asthma. CyclicAMP can also be elevated by inhibit-ing the enzyme(s), termed phospho-diesterase (PDE), that degrade it.Although PDEs comprise a ten-membersuperfamily, it is PDE4 that is the pre-dominant isoenzyme in immune andpro-inflammatory cells, and it is a majorcontributor to cyclic AMP metabolism inairways smooth muscle.
First generation PDE4 inhibitors suchas rolipram are active across a broadspectrum of disease models. However,their therapeutic utility is limited by un-wanted side effects, predominantly nau-sea, vomiting and gastric acid secretion.