antiviral chemistry & chemotherapyâ€™s current antiviral agents

Antiviral Chemistry & Chemotherapy’s current antiviralagents FactFile 2006 (1st edition)

The RNA viruses

RNA_title_sheet 22/8/06 10:13

RNA_title_sheet 22/8/06 10:13

©2006 International Medical Press

Antiviral Chemistry & Chemotherapy 17.3

Amantadine

Oseltamivir

Symmetrel, Mantadix

Tamiflu

Principal target virus: Influenza A virus.

Other activities: HCV.

Mode of action: M2 ion channel inhibitor.

Clinical stage: Licensed.

Adamantine (cyclic primary amine) derivative used for the treatmentand prophylaxis of influenza A virus infections. Rapid emergence ofresistence has limited it use. Sometimes used to treat HCV infectionin combination with interferon and ribavirin.


Other activities: Influenza B virus.

Mode of action: Influenza virus neuraminidase inhibitor.


Sialic acid analogue used for the treatment and prophylaxis ofinfluenza A and B virus infection. Also effective against avianinfluenza H5N1 virus. In contrast with zanamivir, oseltamivir can begiven perorally.

Novartis

Gilead Sciences/Roche

Adamantan-1-amine hydrochloride, l-adamantanamine, aman-tadine hydrochloride.

Ethyl ester of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethyl-propoxy)-1-cyclohexane-1-carboxylic acid, GS4104, Ro-64-0796.

References: 1,64,65

References: 70,71,72

H

H

NH2.HCIH

OO

O

ONH2

HN

Ciluprevir

O

O

N

NH

HN

HN

N

N

S

O

O

O

O

OH

OMe

H3C

CH3

Principal target virus: HCV

Mode of action: PI

Development of ciluprevir has been discontinued.Ciluprevir is a novel small molecule anti-hepatitis C compound. It isthe first in a new class of investigational antiviral drugs, HCV PIs.

Boehringer Ingelheim (Canada) Ltd. R&D(1S,4R,6S,14S,18R)-7Z-14-Cyclopentyloxycarbonylamino-18-[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid,BILN 2061. References: 66,67,68,69

FFFF aaaa cccc tttt FFFF iiii llll eeee :::: RRRR NNNN AAAA vvvv iiii rrrr uuuu ssss eeee ssss

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Peramivir

O

OH

NH

NH2

HN

HN

HO

HO

Principal target virus: Influenza virus.


Clinical stage: Phase III trials versus influenza virus.

Peramivir showed significant antiviral activity versus influenza A and B in Phase II and III clinical trials, but the primary endpoint oftime to relief of symptoms did not reach statistical significance possibly due to low bioavailability. Threat of H5N1 has renewed interestin probability of using an oral prodrug.

BioCryst Pharamaceuticals, Inc(1S,2S,3S,4I)-3-[(1S)-1-Acetylamino)]-2-hydroxy-cyclopentanecarboxylic acid, RWJ-270201, BCX-1812.

References: 73,74

Pirodavir

CH3 CH2 CH2 CH2 CH3O C

O

ON

N N

Principal target virus: Human rhinovirus groups A and B.

Other activities: Some enteroviruses.

Mode of action: Capsid-binding compound.

Clinical stage: Discontinued.

Janssen PharmaceuticaEthyl-4-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate,R77975.

References: 75,76


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RibavirinVirazid/Virazide/Virazole

Principal target virus: RSV, HCV.

Other activities: Influenza virus, lassa, hantaan and others.

Mode of action: Inosine monophosphate dehydrogenase inhibitor,inhibitor of influenza virus RNA polymerase.

Clinical stage: Licensed, patent expired.

Known to have additional immunosuppressive effects.

Schering–Plough (formerly ICN Pharmaceuticals)1-β-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, ICN-1229,RTCA, tribavirin.


NN

N

OHO

HO OH

H2N

O

Pleconaril

R1479

O

O

N

NHO

HO OH

N3

NH2

O N

NFF

F

CH3

CH3

O

NO

CH3

Principal target virus: Rhinoviruses.

Mode of action: Capsid-binding protein.

Other activities: Enteroviruses, coxsackievirus.

Clinical stage: Discontinued.

Capsid-binding agent, structurally related to WIN 54954. Withdrawndue to toxicity concerns (induces cytochrome P-450 3A enzymes).

Principal target virus: HCV.

Mode of action: R1479 triphosphate inhibits the HCV polymeraseNS5B.

Clinical stage: Completed SAD and MAD Phase I clinical trials.

In MAD studies with HCV infected patients, R1479 was well toler-ated and showed modest viral load reductions at the higher dosingregimens. Due to low exposure, R1479 was discontinued in favourof a R1479 prodrug, R1626.

ViroPharma

Roche

3-[3,5-Dimethyl-4-[3-(3-methyloxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole, VP-63843.

4′-Azidocytidine.

References: 77,78

References: 79,80


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T-705

Ruprintrivir

Rimantadine Flumadine

O

COOEt

O

F

ONH

HN NH

O

O

N

H

H

NH2.HCI

CH3

H

OHN

NF CONH2

Principal target virus: Influenza.

Other activities: Parainfluenza.

Mode of action: Influenza virus RNA polymerase inhibitor.

Clinical stage: Preclinical.

Investigative new drug application in progress.

Principal target virus: Rhinovirus.

Other activities: Enterovirus.

Mode of action: 3C protease inhibtor.

Clinical stage: Phase II.

Demonstration of efficacy in Phase II human experimentalhuman rhinovirus challenge trial, but not in a subsequent Phase IInatural infection study in patients and thus was terminated forclinical development.


Mode of action: M2 ion channel inhibitor.


Adamantane derivative. Related to amantadine with which itshows cross-resisitence. Rapid emergence of resistence has limitedit use.

Pfizer Global Research and Development

Toyama Chemical Co., Ltd

Forest Pharmaceuticals1-(1-Adamantyl)ethanamine hydrochloride.

4-{2-(4-Fluoro-benzyl)-6-methyl-5-[(5-methyl-isoxazole-3-carbonyl)-amino]-4-oxo-heptanoylamino}-5-(2-oxo-pyrro-lidin-3-yl)-pent-2-enoic acid ethyl ester, AG7088.

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide.



References: 1,65,84


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TelaprevirVX 950

HN

HN

HN

NH

N

NN

O

O

O

OO

O


Mode of action: HCV NS3•4A inhibitor.

Vertex Pharmaceuticals(1S, 3aR, 6aS)-2-((S)-2-{(S)-2-Cyclohexyl-2-[(pyrazine-2-car-bonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid ((S)-1-cyclopropylaminooxa-lyl-butyl)-amide, VRT-111950, LY570310, MP-424, CAS RegistryNumber 402957-28-2.


Valopicitabine

N

N

NH2

O

OHO

O OH

O

NH2

CH3


Mode of action: Nucleoside analogue.

Clinical stage: Phase IIb clinical trials.

Oral prodrug active against HCV-1 infection in the clinic and shows enhanced efficacy in combination with interferon α. Also activeagainst bovine virus diarrhoea virus in vitro.

Idenix Pharmaceuticals/Novartis Pharmaceuticals2(S)-Amino-3-methyl-butyric acid, 5(R)-[4-amino-2-oxo-2H-pyrimidine-1-yl]-4(R)-hydroxy-2(R)-hydroxymethyl-4-methyl-tetrahydro-furan-3(S)-yl ester (dihydrochloride salt), NM 283, 3'-valine ester of 2'-C-methylcytidine, 2′-C-methyl-cytidine-3′-O-L-valine ester (dihydrochloride salt).

References: 94,95


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Principal target virus: Rhinoviruses.

Other activities: Enteroviruses.

Mode of action: Capsid-binding agent.

Clinical stage: No longer in development.

WIN 54954

Sterling Winthrop5-(5-[2,6-Dichloro-4-94,5-dihydro-2-oxazolyl)phenoxy]-pentyl)-3-methylisoxasole.

References: 100,101

O

N

Cl

Cl

O

O

N

CH3

Viramidine

N

N

N

HO

NH

H2N

O

HO OH


Other activities: Influenza virus. Members of Bunyaviridae (rift valley fever, sandfly fever, crimean-congo haemorrhagic fever, hantaan virusinfection).

Mode of action: Inosine monophosphate dehydrogenase inhibitor, inhibitor of influenza virus RNA polymerase.

Clinical stage: Phase III versus hepatitis C.

Viramidine is a prodrug of ribavirin

Valeant Pharmaceuticals, Inc1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboximidine, ribamidine.

References: 96,97,98,99


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ZanamivirRelenza

OHOH

OH

H

OH

HN

O

O

HN NH2

NH

O

Principal target virus: Influenza A viruses.

Other activities: Influenza B viruses.



Sialic acid analogue used for the treatment and prophylaxis ofinfluenza A and B virus infections. Delivered by inhalation owing topoor oral bioavailability.

GlaxoSmithKline (GSK)(4R,5R,6R)-5-acetamido-4-(diaminomethylideneamino)-6-[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro-4H-pyran-2-car-boxylic acid, 4-guanidino-Neu5Ac2en, GG167, GR121167X.

References: 102,103



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Disclaimer

The authors declare that the current antiviral agentFactFile is accurate and up-to-date to the best of theirknowledge.The authors are happy to receive any commentsor any information about new compounds for inclusion infuture editions, please do not hesitate to contact us by usingthe feedback form provided at the start of the FactFile.

Acknowledgements

The authors would like to acknowledge the followingindividuals for contributing information and their time:Irina Alymova, Koen Andries, Karen K Biron, DavidChu, Marc S Collett, Richard J Colonno, Jose Este, AnnKwong, Daniel Lamarre, Richard Mackman, Victor EMarquez, Bo Öberg, Amy Patick, Robert Sidwell, DavidB Smith, Jean-Pierre Sommadossi, David D Standingand Stephen Villano.

The authors would also like to thank Emdadur Rahmanfor all his editorial assistance and Harminder Malah forhis illustrations.

References

1. De Clercq E (2004) Antiviral drugs in current clinical use.Journal of Clinical Virology 30:115–133.

2. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L& Schaeffer HJ (1977) Selectivity of action of an antiherpeticagent 9-(2-hydroxyethoxymethyl)guanine. Proceedings of theNational Academy of Sciences of the United States of America74:5716–5720.

3. Wagstaff AJ, Faulds D & Goa KL (1994) Aciclovir. A reap-praisal of its antiviral activity, pharmacokinetic properties andtherapeutic efficacy. Drugs 47:153–205.

4. Pauwels R, Balzarini J, Schols D, Baba M, Desmyter J,Rosenberg I, Holy A & De Clercq E (1988)Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrobial Agents &Chemotherapy 32:1025–1030.

5. Arends S, Vanhalteren E, Kamp W & Schokker J (1996) Safetyof 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in patientswith human immunodeficiency virus infection – a pilot study.Pharmacy World & Science 18:30–34.

6. Naesens L, Balzarini J, Bischofberger N & De Clercq E (1996)Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxethyl)adenine, thebis (pivaloyloxymethyl) ester prodrug of 9-(2-phosphonyl-methoxyethyl) adenine. Antimicrobial Agents and Chemotherapy40:22–28.

7. Heijtink RA, De Wilde GA, Kruining J, Berk L, Balzarini J,De Clercq E, Holy A & Schalm SW (1993) Inhibitory effectof 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on humanand duck hepatitis B virus infection. Antiviral Research21:141–153.

8. De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS &Walker RT (1979) (E)-5-(2-bromovinyl)-2′-deoxyuridine: apotent and selective antiherpes agent. Proceedings of the NationalAcademy of Sciences of the United States of America 76:2947–2951.

9. De Clercq E, Degreef H, Wildiers J, De Jonge G, DrochmansA, Descamps J & De Somer P (1980) Oral (E)-5-(2-bro-

movinyl)-2′-deoxyuridine in severe herpes zoster infections.British Medical Journal 281:1178.

10. De Clercq E (2004) Discovery and development of BVDU(brivudin) as a therapeutic for the treatment of herpes zoster.Biochemical Pharmacology 68:2301–2315.

11. De Clercq E (2003) Clinical potential of the acyclic nucleosidephosphonates cidofovir, adefovir, and tenofovir in treatment ofDNA virus and retrovirus infections. Clinical MicrobiologyReviews 16:569–596.

12. De Clercq E, Sakuma T, Baba M, Pauwells R, Balzarini J,Rosenberg I & Holy A (1987) Antiviral activity of phosphonyl-methoxyalkyl derivatives of purine and pyrimidines. AntiviralResearch 8:261–272.

13. Lalezari JP, Jaffe HS, Stagg RJ, Ruby AE, Wolitz RA, SimonGL, Weinberg DV, Lewis RA, Johnson M, Youle M, NorthfeltDW, Kuppermann BD, Hardy WD, Nelson R, Ives DV,Kemper CA, McKinley GF, Kramer F & Holland GN (1998)Randomized, controlled study of the safety and efficacy ofintravenous cidofovir for the treatment of relapsingcytomegalovirus retinitis in patients with AIDS. Journal ofAcquired Immune Deficiency Syndromes and Human Retrovirology17:339–344.

14. Chu CK, Ma TW, Shanmuganathan K, Wang CG, Xiang YJ,Pai SB, Yao GQ & Cheng YC (1995) Use of 2′-Fluoro-5-methyl-beta-L-arabinofurano-syluridine(L-FMAU) as a novelantiviral agent for hepatitis B and Epstein-Barr virus,Antimicrobial Agents and Chemotherapy 39: 979–981.

15. Hu R, Li L, Degrève B, Dutschman GE, Lam W & ChengYC (2005) Behavior of thymidylate kinase toward monophos-phate metabolites and its role in the metabolism of 1-(2′-deoxy-2′-fluoro-L-l-arabinofuranosyl)-5-methyluracil (clevu-dine) and 2′,3′-didehydro-2′,3′-dideoxythymidine in cells.Antimicrobial Agents and Chemotherapy 49:2044–2049.

16. Marcellin P, Mommeja-Marin H, Sacks SL, Lau GKK, SereniD, Bronowicki J-P, Conway B, Trepo C, Blum MR, Yoo BC,Mondou E, Sorbel J, Snow A, Rousseau F & Lee H-S (2004)A phase II dose-escalating trial of clevudine in patients withchronic hepatitis B. Hepatology 40:140–148.

17. De Clercq E (2005) Emerging anti-HIV drugs. Expert Opinionin Emerging Drugs 10:241–274.

18. Rajagopalan P, Boudinot FD, Chu CK, Tennant BC, BaldwinBH & Schinazi RF (1996) Pharmacokinetics of (–)-beta-D-2,6-diaminopurine dioxolane and its metabolite dioxolaneguanosine in woodchucks. Antiviral Chemistry andChemotherapy 7:65–70.

19. Mitsuya H, Popovic M, Yarchoan R, Matsushita S, Gallo RC &Broder S (1984) Suramin protection of T cells in vitro againstinfectivity and cytopathic effect of HTLV-III. Science226:172–174.

20. Bridges EG, Dutschman GE, Gullen EA & Cheng YC (1996)Favorable interaction of beta-L(-) nucleoside analogues withclinically approved anti-HIV nucleoside analogues for thetreatment of human immunodeficiency virus. BiochemicalPharmacology 51:731–736.

21. Furman PA, Davis M, Liotta DC, Paff M, Frick LW, NelsonDJ, Dornsife RE, Wurster JA, Wilson LJ & Fyfe JA (1992)The anti-hepatitis B virus activities, cytotoxicities and anabolicprofiles of the (–) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl)]cytosine. AntimicrobialAgents and Chemotherapy 36:2686–2692.

22. Chang TT, Gish RG., deMan R, Gadano A, Sollano J, ChaoYC, Lok AS, Han KY, Goodman Z, Zhu J, Cross A,DeHertogh D, Wilber R, Colonno R & Apelian D (2006) Acomparison of entecavir and lamivudine for HBeAg-positivechronic hepatitis B. New England Journal of Medicine354:1001–1010.

23. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H,Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A,

FFFF aaaa cccc tttt FFFF iiii llll eeee

DNA_RNA 21/8/06 17:47 Page 160


Antiviral Chemistry & Chemotherapy 17.3 FFFF aaaa cccc tttt FFFF iiii llll eeeeColonno R & Fernandes L (2006) Entecavir versus lamivudinefor patients with HBeAg-negative chronic Hepatitis B. NewEngland Journal of Medicine 354:1011–1020.

24. Colonno RJ, Genovesi EV, Medina I, Lamb L, Durham SK,Huang ML, Corey L, Littlejohn M, Locarnini S, Tennant BC,Rose B & Clark JM (2001) Long-term entecavir treatmentresults in sustained antiviral efficacy and prolonged life span inthe woodchuck model of chronic hepatitis infection. Journal ofInfectious Diseases 184:1236–1245.

25. Vere Hodge RA, Sutton D, Boyd MR, Harnden MR & JarvestRL (1989) Selection of an oral prodrug (BRL 42810; famci-clovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; penciclovir]. AntimicrobialAgents and Chemotherapy 33:1765–1773.

26. Perry CM & Wagstaff AJ (1995) Famciclovir. A review of itspharmacological properties and therapeutic efficacy in her-pesvirus infections. Drugs 50:396–415.

27. Dworkin RH, Boon RJ, Griffin RG & Phung D (1998)Postherpetic neuralgia: Impact of famciclovir, age, rash severityand acute pain in herpes zoster patients. Journal of InfectiousDiseases 178:S76–S80.

28. Azad RF, Driver VB, Tanaka K, Crooke RM & Anderson KP(1993). Antiviral activity of a phosphorothioate oligonucleotidecomplementary to RNA of the human cytomegalovirus majorimmediate-early region. Antimicrobial Agents and Chemotherapy37:1945–1954.

29. Flores-Aguilar M, Freeman WR, Wiley CA, Gangan P,Munguia D, Tatebayashi M; Vuong C & Besen G (1997)Evaluation of retinal toxicity and efficacy of anti-cytomegalovirus and anti-herpes simplex virus antiviral phos-phorothioate oligonucleotides ISIS 2922 and ISIS 4015. Journalof Infectious Diseases 175:1308–1316.

30. Helgstrand E, Eriksson B, Johansson NG, Lannerö B, LarssonA, Misiorny A, Norén JO, Sjöberg B, Stenberg K, Stening G,Stridh S, Öberg B, Alenius S & Philipson L (1978) Trisodiumphosphonoformate, a new antiviral compound. Science201:819–821.

31. Wagstaff AJ & Bryson HM (1994) Foscarnet. A reappraisal ofits antiviral activity, pharmacokinetic properties and therapeuticuse in immunocompromised patients with viral infections.Drugs 48:199–226.

32. Smith KO, Galloway KS, Kennell WL, Ogilvie KK & RadatusBK (1982). A new nucleoside analog, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, highly active in vitro against herpessimplex virus types 1 and 2. Antimicrobial Agents andChemotherapy 22:55–61.

33. Spector SA, McKinley GS, Lalezari JP, Samo T, Andruczk R,Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W,Wong R & Stempien MJ (1996) Oral ganciclovir for the pre-vention of cytomegalovirus disease in persons with AIDS. NewEngland Journal of Medicine 334:1491–1497.

34. De Clercq E & Field HJ (2006) Antiviral prodrugs – the devel-opment of sucessful prodrug strategies for antiviral chemotherapy.British Journal of Pharmacology 147:1–11.

35. Smith KO & Dukes CD (1964) Effects of 5-iodo-2′-deoxyuri-dine (IDU) on herpesvirus synthesis and survival in infectedcells. Journal of Immunology 92:550–554.

36. Spruance SL, Stewart JCB, Freeman DJ, Brightman VJ, CoxJL, Wenerstrom G, McKeough MB & Rowe NH (1990) Earlyapplication of topical 15% idoxuridine in dimethyl sulfoxideshortens the course of herpes simplex labialis: a multicenterplacebo-controlled trial. Journal of Infectious Diseases161:191–197.

37. Harrison CJ, Jenski L, Voychehovski T & Bernstein DI (1998)Modification of immunological responses and clinical diseaseduring topical R-837 treatment of genital HSV-2 infection.Antiviral Research 10:209–224.

38. Beutner KR, Douglas JM Jr, Owens ML, Fox TL, HoughamAJ & Spruance SL (1998) Treatment of genital warts with animmune-response modifier (imiquimod). Journal of the AmericanAcademy of Dermatology 38:230–239.

39. Doong SL, Tsai CH, Schinazi RF, Liotta DC & Cheng YC(1991) Inhibition of the replication of hepatitis B virus in vitroby 2′,3′-dideoxy-3′-thiacytidine and related analogues.Proceedings of the National Academy of Sciences of the United Statesof America 88:8495–8499.

40. Nevens F, Thomas HC, De Man RA, Fevery J, Sullivan MT,Barber J, Tyrrell DL, Honkoop P & Main J (1997)Lamivudine therapy for chronic hepatitis B: a six-month ran-domized dose-ranging study. Gastroenterology113:1258–1263.

41. Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA3rd, Davis MG, Talarico CL, Miller WH, Ferris R, DornsifeRE, Stanat SC, Drach JC, Townsend LB & Koszalka GW(2002) Potent and selective inhibition of humancytomegalovirus replication by 1263W94, an benzimidazole L-riboside with a unique mode of action. Antimicrobial Agents andChemotherapy 46:2365–2372.

42. Krosky PM, Baek MC & Coen DM (2003). The humancytomegalovirus UL97 protein kinase, an antiviral drug target,is required at the stage of nuclear egress. Journal of Virology77:905–914.

43. Koszalka GW, Johnson NW, Good SS, Boyd L, ChamberlainSC, Townsend LB, Drach JC & Biron KK (2002) Preclinicaland toxicology studies on 1263W94, a potent and selectiveinhibitor of human cytomeglovirus replication. AntimicrobialAgents and Chemotherapy 46:2373–2380.

44. Chou S, Marousek GI, Senters AE, Davis MG & Biron KK(2004). Mutations in the human cytomegalovirus UL27 geneconfer resistance to maribavir. Journal of Virology 78:7124–7130.

45. Komazin G, Ptak RG, Emmer BT, Townsend LB & Drach JC(2003) Resistance of human cytomegalovirus to the benzimida-zole L-ribonucleoside maribavir maps to UL27. Journal ofVirology 77:11499–11506.

46. Lalezari JP, Aberg JA, Wang LH, Wire MB, Minor R,Snowden W, Talarico CL, Shaw S, Jacobson MA & Drew WL(2002) Phase I dose escalation trial evaluating the pharmacoki-netics, anti-human cytomegalovirus (HCMV) acitivty, andsafety of 1263W94 in human immunodeficiency virus-infectedmen with aymptomatic HCMV shedding. Antimicrobial Agentsand Chemotherapy 46:2969–2976.

47. Wang LH, Peck RW, Yin Y, Allanson J, Wiggs R & Wire MB(2003) Phase I safety and pharmacokinetic trial of 1263W94, anovel, oral anti-human cytomegalovirus agent, in healthy andhuman immunodeficiency virus-infected subjects. AntimicrobialAgents and Chemotherapy 47:1334–1342.

48. ViroPharma announces positive phase 2 results demonstratingthat maribavir significantly reduces CMV reactivation [Pressrelease]. Exton: ViroPharma Incorporated [cited 29 March2006]. Available from http://phx.corporate-ir.net/phoenix.zhtml?c=92320&p=irol-news2006

49. Boyd MR, Bacon TH, Sutton D & Cole M (1987)Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) in cell culture. Antimicrobial Agentsand Chemotherapy 31:1238–1242.

50. Spruance SL, Boon R, Saltzman R, Tucker R, Thoming C &Rea TL (1997) Penciclovir cream for the treatment of herpessimplex labialis. A randomized, multicenter, double-blind,placebo-controlled trial. Topical Penciclovir Collaborative StudyGroup. Journal of the American Medical Association277:1374–1379.

51. Degreef H & Famciclovir Herpes Zoster Clinical Study Group(1994) Famciclovir, a new oral antiherpes drug: results of thefirst controlled clinical study demonstrating its efficacy and

DNA_RNA 21/8/06 17:47 Page 161



safety in the treatment of uncomplicated herpes zoster inimmunocompetent patients. International Journal ofAntimicrobial Agents 4:241–246

52. Rusconi S, Moonis M, Merrill DP, Pallai PV, Neidhardt EA,Singh SK, Willis KJ, Osburne MS, Profy AT, Jenson JC &Hirsch MS (1996). Naphthalene sulfonate polymers withCD4-blocking and anti-human immunodeficiency virus type1 activities. Antimicrobial Agents & Chemotherapy 40:234–236.

53. De Clercq E (2006) A guided tour through the antiviral drugfield. Future Virology 1:19–35.

54. Balzarini J, Holy A, Jindrich J, Naesens L, Snoeck R, Schols D& De Clercq E (1993) Differential antiherpesvirus and anti-retrovirus effects of the (S) and (R) enantiomers of acyclicnucleoside phosphonates: potent and selective in vitro and invivo antiretrovirus activities of (R)-9-(2-phospho-nomethoxypropyl)-2,6-diaminopurine. Antimicrobial Agents &Chemotherapy 37: 332–338.

55. Tsai CC, Follis KE, Sabo A, Beck TW, Grant RF,Bischofberger N, Benvenista R & Black R (1995) Prevention ofSIV infection in macaques by (R)-9-(2-phosphonyl-methoxypropyl)adenine. Science 270:397–399.

56. Deeks SG, Barditch-Crovo P, Lietman PS, Hwang F, CundyKC, Rooney JF, Hellmann NS, Safrin S & Kahn JO (1998)Safety, pharmacokinetics, and antiretroviral activity of intra-venous 9- [2-(R)-(Phosphonomethoxy)propyl]adenine, a novelanti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrobial Agents & Chemotherapy42:2380–2384.

57. Naesens L, Bischofberger N, Augustijns P, Annaert P, Van denMooter G, Arimilli MN, Kim CU & De Clercq E (1998).Antiretroviral efficacy and pharmacokinetics of oral bis(iso-propyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrobial Agents & Chemotherapy42:1568–1573.

58. Birch CJ, Tyssen DP, Tachedjian G, Doherty R, Hayes K,Mijch A & Lucas CR (1992) Clinical effects and in vitro stud-ies of trifluorothymidine combined with interferon-a for treat-ment of drug-resistant and -sensitive herpes simplex virusinfections. Journal of Infectious Diseases 166:108–112.

59. Kessler HA, Korvick JA, Nevin T, Owens S, Wettlaufer B,McKinley GF, Cheeseman SH, Steigbigel RT, Safrin S, BaileyTC, Kuritzkes DR, Feinberg J, Benson CA, Farthing C &Hurwitz S (1996) Pilot study of topical trifluridine for thetreatment of acyclovir-resistant mucocutaneous herpes simplexdisease in patients with AIDS (ACTG 172). AIDS ClinicalTrials Group. Journal of Acquired Immune Deficiency Syndromesand Human Retrovirology 12:147–152.

60. Beauchamp LM, Orr GF, de Miranda P, Burnette T &Krenitsky TA (1992) Amino acid esters prodrugs of aciclovir.Antiviral Chemistry & Chemotherapy 3:157–164.

61. Beutner KR (1995) Valaciclovir: a review of its antiviral activity,pharmacokinetic properties, and clinical efficacy. AntiviralResearch 28:281–290.

62. Schabel FM (1968) The antiviral activity of 9-beta-D-arabino-furanosyladenine (ara-A). Chemotherapy 13:321–338.

63. Buchanan RA & Hess F (1985). Vidarabine (Vira-A): pharma-cology and clinical experience. In Viral Chemotherapy, vol. 2; pp.109–143. Edited by D Hugar. Oxford: Pergamon Press.

64. Davies WL, Grunert RR, Miles HB, Davies LM, GrahamNMH, Ryan P, Warwick DA & Albrecht JK (1964) Antiviralactivity of 1-adamantanamine (amantadine). Science144:862–863.

65. Monto AS (1995) Viral respiratory infections in the communi-ty: epidemiology, agents and interventions. American Journal ofMedicine 99:24S–27S.

66. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G,Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG,

Faucher AM, Goudreau N, Kawai SH, Kukolj G, Lagace L,LaPlante SR, Narjes H, Poupart MA, Rancourt J, Sentjens RE,St George R, Simoneau B, Steinmann G, Thibeault D,Tsantrizos YS, Weldon SM, Yong CL & Llinas-Brunet M(2003) An NS3 protease inhibitor with antiviral effects inhumans infected with hepatitis C virus. Nature 426:186–189.

67. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M,Sentjens RE, Calleja JL, Forns X, Erhardt A, Cronlein J,Chaves RL, Yong CL, Nehmiz G & Steinmann GG (2004)Short-term antiviral efficacy of BILN 2061, a hepatitis C virusserine protease inhibitor, in hepatitis C genotype 1 patients.Gastroenterology 127:1347–1355.

68. Reiser M, Hinrichsen H, Benhamou Y, Reesink HW,Wedemeyer H, Avendano C, Riba N, Yong CL, Nehmiz G &Steinmann GG (2005) Antiviral efficacy of NS3-serine pro-tease inhibitor BILN-2061 in patients with chronic genotype 2and 3 hepatitis C. Hepatology 41:832–835.

69. Llinas Brunet M, Bailey M, Bolger G, Brochu C, Faucher AM,Garneau M, Ghiro E, Gorys V, Grand Maitre C, Halmos T,Lapeyre-Paquette N, Liard F, Rhéaume M and Lamarre D(2004) Structure-activity study on a novel series of macrocyclicinhibitors of the hepatitis C virus NS3 protease leading to thediscovery of BILN 2061. Journal of Medicinal Chemistry47:1605–1608.

70. Kim CU, Lew N, Williams MA, Liu H, Zhang L,Swaminathan S, Bischofberger N, Chen MS, Mendel DB, TaiCY, Laver WG & Stevens RC (1997) Influenza neuraminidaseinhibitors posessing a novel hydrophobic interaction ion theenzyme active site: design, synthesis and structural analysis ofcarbocyclic sialic acid analogues with potent anti-influenzaactivity. Journal of the American Chemical Society 119:681–690.

71. Hitchcock MJM (1996) GS4104: A new orally administeredanti-influenza drug candidate. International Antiviral News 4:175.

72. Ward P, Small I, Smith J, Suter P & Dutkowski R (2005).Oseltamivir (Tamiflu) and its potential for use in the event ofan influenza pandemic. Journal of Antimicrobial Chemotherapy 55(Suppl 1):i5–i21.

73. Sidwell RW & Smee DF (2002) Peramivir (BCX-1812, RWJ-270201): Potential new therapy for influenza. Expert Opinionon Investigational Drugs 11:859–869.

74. Bantia S, Arnold CS, Parker CD, Upshaw R & Chand P(2006) Anti-influenza virus activity of peramivir in mice withsingle intramuscular injection. Antiviral Research 69:39–45.

75. Andries K, Dewindt B, Snoekes J, Willebrords R, Van EemerenK, Stokbroekx R & Janssen PAJ (1992) In vitro activity of piro-davir (R 77975), a substituted phenoxy-pyridazinamine withbroad-spectrum antipicornaviral activity. Antimicrobial Agentsand Chemotherapy 36:100–107.

76. Hayden FG, Hipskind GJ, Woerner DH, Eisen GF, JanssensM, Janssen PAJ & Andries K (1995) Intranasal pirodavir(R77,975) treatment of rhinovirus colds. Antimicrobial Agentsand Chemotherapy 39:290–294.

77. Diana GD, Rudewicz P, Pevear DC, Nitz TJ, Aldous SC,Aldous DJ, Robinson DT, Draper Tdutko FJ, Aldi C, GendronG, Oglesby RC, Volkots DL, Reuman M, Bailey TR, CzerniakR, Block T, Roland R & Oppermann J (1995) Picornavirusinhibitors: trifluoromethyl substitution provides a global protec-tive effect against hepatic metabolism. Journal of MedicinalChemistry 38:1355–1371.

78. Diana GD & Pevear DC (1997) Antipicornavirus drugs: cur-rent status. Antiviral Chemistry and Chemotherapy 8:401–408.

79. Klumpp K, Leveque V, Le Pogam S, Ma H, Jiang W-R, KangH, Granycome C, Singer M, Laxton C, Qi Hang J, Sarma K,Smith DB, Heindl D, Hobbs CJ, Merrett JH, Symons J,Cammack N, Martin JA, Devos R, Najera I (2006) The novelnucleoside analog R1479 (4′-Azidocytidine) is a potentinhibitor of NS5B -dependent RNA synthesis and hepatitis C


DNA_RNA 21/8/06 17:47 Page 162


Antiviral Chemistry & Chemotherapy 17.3 FFFF aaaa cccc tttt FFFF iiii llll eeeevirus replication in cell culture. Journal of Biological Chemistry281:3793.

80. Le Pogam S, Jiang W-R, Leveque V, Rajyaguru S, Ma H, KangH, Jiang S, Singer M, Ali S, Klumpp K, Smith D, Symons J,Cammack N, Najera I (2006) In vitro selected Con1 subge-nomic replicons resistant to 2′-C-Me-Cytidine or to R1479show lack of cross resistance. Virology 351: 349–359.

81. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT& Robins RK (1972). Broad-spectrum antiviral activity ofVirazole: 1-beta-D-Ribofuranosyl-1,2,4,-triazole-3-carboxam-ide. Science 177:705–706.

82. Randolph AG & Wang EE (1996) Ribavirin for respiratory syn-cytial virus lower respiratory tract infection. A systematicoverview. Archives of Pediatric and Adolescent Medicine150:942–947.

83. Leyssen P, De Clercq E & Neyts J (2006) The anti-yellow fevervirus activity of ribavirin is independent of error-prone replica-tion. Molecular Pharmacology 69:1461–1467.

84. Wintermeyer SM & Nahata MC (1995) Rimantadine: a clini-cal perspective. Annals of Pharmacotherapy 29:299–310.

85. Dragovich PS, Prins TJ, Zhou R, Webber SE, Marakovits JT,Fuhrman SA, Patick AK, Matthews DA, Lee CA, Ford CE,Burke BJ, Rejto PA, Hendrickson TF, Tuntland T, Brown EL,Meador JW 3rd, Ferre RA, Harr JE, Kosa MB & WorlandST (1999) Structure-based design, synthesis, and biologicalevaluation of irreversible human rhinovirus 3Cprotease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. Journal of Medicinal Chemistry42:1213–1224.

86. Patick AK, Binford SL, Brothers MA, Jackson RL, Ford CE,Diem MD, Maldonado F, Dragovich PS, Zhou R, Prins TJ,Fuhrman SA, Meador JW, Zalman LS, Matthews DA &Worland ST (1999) In vitro antiviral activity of AG7088, apotent inhibitor of human rhinovirus 3C protease. AntimicrobialAgents & Chemotherapy 43:2444–2450.

87. Hayden FG, Turner RB, Gwaltney JM, Chi-Burris K, GerstenM, Hsyu P, Patick AK, Smith GJ 3rd & Zalman LS (2003)Phase II, randomized, double-blind, placebo-controlled studies ofruprintrivir nasal spray 2-percent suspension for prevention andtreatment of experimentally induced rhinovirus colds in healthyvolunteers. Antimicrobial Agents and Chemotherapy 47:3907–3916.

88. Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T,Kozaki K, Nomura N, Egawa H, Mionami S, Watanabe Y,Narita H & Shiraki K (2002) In vitro and in vivo activities ofanti-influenza compound T-705. Antimicrobial Agents &Chemotherapy 46:977–981.

89. Takahashi K, Furuta Y, Fukuda Y, Kuno M, Kamiyama T,Kozaki K, Nomura N, Egawa H, Minami S & Shiraki K(2003) In vitro and in vivo activities of T-705 and oseltamiviragainst influenza virus. Antiviral Chemistry & Chemotherapy14:235–241.

90. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H,Uehara S, Kozaki K, Nomura N, Egawa H & Shiraki K(2005) Mechanism of action of T-705 against influenza virus.Antimicrobial Agents & Chemotherapy 49:981–986.

91. Perni RB, Almquist SJ, Byrn RA, Chandorkar G, ChaturvediPR, Courtney LF, Decker CJ, Dinehart K, Gates CA,Harbeson SL, Heiser A, Kalkeri G, Kolaczkowski E, Lin K,Luong YP, Rao BG, Taylor WP, Thomson JA, Tung RD, WeiY, Kwong AD & Lin C (2006) Preclinical profile of VX-950, apotent, selective, and orally bioavailable inhibitor of hepatitis Cvirus NS3-4A serine protease. Antimicrobial Agents andChemotherapy 50:899–909.

92. Lin C, Lin K, Luong YP, Rao BG, Wei YY, Brennan DL,Fulghum JR, Hsiao HM, Ma S, Maxwell JP, Cottrell KM,Perni RB, Gates CA & Kwong AD (2004) In vitro resistancestudies of hepatitis C virus serine protease inhibitors, VX-950and BILN 2061: structural analysis indicates different resis-

tance mechanisms. Journal of Biological Chemistry279:17508–17514.

93. Lin C, Gates CA, Rao BG, Brennan DL, Fulghum JR, LuongYP, Frantz JD, Lin K, Ma S, Wei YY, Perni RB & Kwong AD(2005) In vitro studies of cross-resistance mutations against twohepatitis C virus serine protease inhibitors, VX-950 and BILN2061. Journal of Biological Chemistry 280:36784–36791.

94. Afdhal N, Godofsky E & Dienstag J (2004) Final phase I/IItrial results for NM283, a new polymerase inhibitor for hepati-tis C: antiviral efficacy and tolerance in patients with HCV-1infection, including previous interferon failures. Hepatology40:726A.

95. Dieterich D, Lawitz E, Nguyen T, Younes Z, Santoro J, GiltlinN, McEniry D, Chasen R, Goff J, Knox S, Kleber K, BelangerB & Brown N (2006) Early clearance of HCV RNA with val-opicitabine (NM283) plus peg-interferon in treatment-naïvepatients with HCV-1 infection: first results from a phase IIbtiral. Journal of Hepatology 44 (Suppl 2): S271, 736A.

96. Sidwell RW, Bailey KW, Wong MH, Barnard DL & Smee DF(2005). In vitro and in vivo influenza virus-inhibitory effects ofviramidine. Antiviral Research 68:10–17.

97. Sidwell RW, Huffman, JH, Barnard, DL, Pifat DY (1988)Effects of ribamidine, a 3-carboxamidine derivative of ribavirin,on experimentally induced phlebovirus infections. AntiviralResearch 10:193–207.

98. Wu JZ, Larson G, & Hong Z (2004) Dual-action mechanismof viramidine functioning as a prodrug and as a catabolicinhibitor for ribavirin. Antimicrobial Agents and Chemotherapy48:4006–4008.

99. Wu JZ, Lin CC & Hong, Z (2003) Ribavirin, viramidine, andadenosine deaminiase catalysed drug activation: implication fornucleoside prodrug design. Journal of AntimicrobialChemotherapy 52:543–546.

100. Woods MG, Diana GD, Rogge MC, Otto MJ, Dutko FJ &McKinlay MA (1989). In vitro and in vivo activities of WIN54954, a new broad-spectrum antipicornavirus drug.Antimicrobial Agents and Chemotherapy 33:2069–2074.

101. Fohlman J, Friman G, Ilback NG, Ehrnst A, Eggertsen G,Hyypia T & Pauksen K (1996) Antiviral treatment with WIN54 954 reduces mortality in murine coxsackievirus B3myocarditis. Circulation 94:2254–2259.

102. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B,Van Phan T, Smythe ML, White HF, Oliver SW, Colman PM,Varghese JN, Ryan DM, Woods JM, Bethell RC, Hotham VJ,Cameron JM & Penn C (1993) Rational design of potent siali-dase-based inhibitors of influenza virus replication. Nature363:418–423.

103. Hayden FG, Wightman K, Keene O, Hirst HM, Bohnen AM,Nicholson KG, Aoki FY, Fleming DM, Treanor JJ & OsterhausAD (1997) Efficacy and safety of the neuraminidase inhibitorzanamivir in the treatment of influenzavirus infections. GG167Influenza Study Group. New England Journal of Medicine337:874–880.

104. Daluge SM, Good SS, Faletto MB, Martin MT, Miller WH,Averett DR, St Clair MH, Boone LR, Tisdale M & ReardonJE (1995) 1592U89 succinate – a potent, selective anti-HIVcarboxylic nucleoside. Antiviral Research 26:A228.

105. Weverling GJ, Lange JM, Jurriaans S, Prins JM, Lukashov VV,Notermans DW, Roos M, Schuitemaker H, Hoetelmans RM,Danner SA, Goudsmit J & de Wolf F (1998) Alternative mul-tidrug regimen provides improved suppression of HIV-1 repli-cation over triple therapy. AIDS 12:F117–F122.

106. Vandevelde M, Witvrouw M, Schmit JC, Sprecher S, DeClercq E & Tassignon JP (1996) ADA, a potential anti-HIVdrug. AIDS Research and Human Retroviruses 12:567–568.

107. Rice WG, Turpin JA, Huang M, Clanton D, Buckheit RW Jr,Covell DG, Wallqvist A, McDonnell NB, DeGuzman RN,

DNA_RNA 21/8/06 17:47 Page 163



Summers MF, Zalkow L, Bader JP, Haugwitz RD & SausvilleEA (1997) Azodicarbonamide inhibits HIV-1 replication bytargeting the nucleocapsid protein. Nature Medicine 3:341–345.

108. Goebel FD, Hemmer R, Schmit JC, Bogner JR, De Clercq E,Witvrouw M, Pannecouque C, Valeyev R, Vandevelde M,Margery H & Tassignon JP (2001) Phase I/II dose escalationand randomized withdrawal study with add-on azodicar-bonamide in patients failing on current antiretroviral therapy.AIDS 15:33–45.

109. Balzarini J, Baba M, Pauwels R, Herdewijn P & De Clercq E(1988). Antiretrovirus activity of 3′-fluoro- and 3′-azido-substi-tuted pyrimidine 2′,3′-dideoxynucleoside analogues. BiochemicalPharmacology 37:2847–2856.

110. De Clercq E, Yamamoto N, Pauwels R, Balzarini J, WitvrouwM, De Vreese K, Debyser Z, Rosenwirth B, Peichl P, DatemaR, Thornton D, Skerij R, Gaul F, Padmanabhan S, Bridger G,Henson G & Abrams M (1994). Highly potent and selectiveinhibition of human immunodeficiency virus type 1 by thebicyclam derivative JM3100. Antimicrobial Agents &Chemotherapy 38:668–674.

111. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA,Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E& Moore JP (1998). AMD3100, a small molecule inhibitor ofHIV-1 entry via the CXCR4 co-receptor. Nature Medicine4:72–77.

112. Kim EE, Baker CT, Dwyer MD, Murcko MA, Rao BG, TungRD & Navia MA (1995) Crystal structure of HIV-1 proteasein complex with VX-478, a potent and orally bioavailableinhibitor of the enzyme. Journal of the American Chemical Society117:1181–1182.

113. Adkins JC & Faulds D (1998) Amprenavir. Drugs 55:837–842.

114. Watson C, Jenkinson S, Kazmierski W & Kenakin T (2005)The CCR5 receptor-based mechanism of action of 873140, apotent allosteric noncompetitive HIV entry inhibitor. MolecularPharmacology 67:1268–1282.

115. Lin P-F, Blair W, Wang T, Spicer T, Guo Q, Zhou N, Gong Y-F, Wang H-G, Rose R, Yamanaka G, Robinson B, Li C-B,Fridell R, Deminie C, Demers G, Yang Z, Zadjura L,Meanwell N & Colonno R (2003) A small molecule HIV-1inhibitor that targets the HIV-1 envelope and inhibits CD4receptor binding. Proceedings of the National Academy of Sciencesof the United States of America 100:11013–11018.

116. Ho H-T, Fan L, Nowicka-Sans B, McAuliffe B, Li C-B,Yamanaka G, Zhou N, Fang H, Dicker I, Dalterio R, Gong Y-F, Wang T, Yin Z, Ueda Y, Matiskella J, Kadow J, Clapham J,Colonno R & Lin P-F (2006) Envelope conformationalchanges induced by HIV-1 attachment inhibitors prevent CD4binding and downstream entry events. Journal of Virology80:4017–4025.

117. Currens MJ, Gulakowski RJ, Mariner JM, Moran RA, BuckheitRW Jr, Gustafson KR, McMahon JB, Boyd MR (1996)Antiviral activity and mechanism of action of calanolide Aagainst the human immunodeficiency virus type-1. Journal ofPharmacological Experimental Therapy 279:645–651.

118. Ruckle et al. Clinical safety and pharmacokinetics of (+)-calano-lide A. 6th Conference on Retroviruses and Opportunistic Infections.Chicago, IL, USA, 31 January–4 February 1999. Abstract 606.

119. De Clercq E (2004) New anti-HIV agents in preclinical orclinical development. Frontiers in Medicinal Chemistry1:543–579.

120. Fujiwara T, Sato A, El-Farrash M, Miku S, Abe K, Isaka Y,Kodama M, Wu Y, Chen LB, Harada H, Sgimoto H, HatanakaM & Hinuma Y (1998) S-1153 inhibits replication of knowndrug-resistant strains of human immunodeficiency virus type 1.Antimicrobial Agents and Chemotherapy 42:1340–1345.

121. De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A,Pauwels R, Wigerinck P & de Béthune MP (2005) TMC34, a

novel human immunodeficiency virus type 1 protease inhibitoractive against protease inhibitor-resistant viruses, including abroad range of clinical isolates. Antimicrobial Agents andChemotherapy 49:2314–2321.

122. Dueweke TJ, Poppe SM, Romero DL, Swaney SM, So AG,Downey KM, Althaus IW, Reusser F, Busso M, Resnick L,Mayers DL, Lane J, Aristoff PA, Thomas RC & Tarpley WG(1993) U-90152, a potent inhibitor of human immunodeficien-cy virus type 1 replication. Antimicrobial Agents & Chemotherapy37:1127–1131.

123. Bellman PC (1998) Clinical experience with adding delavirdineto combination therapy in patients in whom multiple antiretro-viral treatment including protease inhibitors has failed. AIDS12: 1333–1340.

124. Mitsuya H & Broder S (1986) Inhibition of the in vitro infec-tivity and cytopathic effect of human T-lymphotropic virustype III/lymphadenopathy-associated virus (HTLV-III/LAV)by 2′,3′-dideoxynucleosides. Proceedings of the National Academyof Sciences of the United States of America 83:1911–1915.

125. Gazzard BG & Moyle GJ (1997) The role of didanosine in themanagement of HIV-1 infection. Antiviral Therapy 2:135–147.

126. Gu Z, Allard B, de Muys JM, Lippens J, Rando RF, Nguyen-Ba N, Ren C, McKenna P, Taylor DL & Bethell RC (2006) Invitro antiretroviral activity and in vitro toxicity profile ofSPD754, a new deoxycytidine nucleoside reverse transcriptaseinhibitor for treatment of human immunodeficiency virusinfection. Antimicrobial Agents and Chemotherapy 50:625–631.

127. Bethell R (2004) Pharmacological evaluation of SPD754, a newNRTI. 13th International Symposium on HIV & EmergingInfectious Diseases. Toulon, France, 3–5 June 2004.

128. Hodge CN, Aldrich PE, Bacheler LT, Chang CH, Eyermann CJ,Garber S, Grubb M, Jackson DA, Jadhav PK, Korant B, Lam PY,Maurin MB, Meek JL, Otto MJ, Rayner MM, Reid C, SharpeTR, Shum L, Winslow DL, Erickson-Viitanen S (1996)Improved cyclic urea inhibitors of the HIV-1 protease: synthesis,potency, resistance profile, human pharmacokinetics and X-raycrystal structure of DMP-450. Chemistry and Biology 4:301–314.

129. Young SD, Britcher SF, Tran LO, Payne LS, Lumma WC, LyleTA, Huff JR, Anderson PS, Olsen DB, Carroll SS, PettiboneDJ, O’Brien JA, Ball RG, Balani SK, Lin JH, Chen I-W, SchleifWA, Sardana VV, Long WJ, Byrnes VW & Emini EA (1995)L-743,726 (DMP-266): a novel, highly potent nonnucleosideinhibitor of the human immunodeficiency virus type 1 reversetranscriptase. Antimicrobial Agents & Chemotherapy39:2602–2605.

130. Baba M, Shigeta S, Tanaka H, Miyasaki T, Ubasawa M, UmezuK, Walker RT, Pauwels R & De Clercq E (1992) Highly potentand selective inhibition of HIV-1 replication by 6-phenyluracilderivatives. Antiviral Research 17:245–264.

131. Piras G, Nakade K, Yuasa S & Baba M (1997) Three-drugcombination of MKC-442, lamivudine and zidovudine in vitro:potential approach towards effective chemotherapy againstHIV-1. AIDS 11:469–475.

132. Kilby JM, Hopkins S,Venetta TM, DiMassimo B, Cloud GA,Lee JY, Alldredge L. Lambert D, Bolognesi D, Matthews T,Johnson Mr, Nowak MA, Shaw GM & Saag MS (1998)Potent suppression of HIV-1 replication in humans by T-20, apeptide inhibitor of gp41-mediated virus entry. Nature Medicine4:1302–1307.

133. Venetta T, DiMassimo B, Johnson MR, Lambert DM, RecnyMA, Hopkins S & Saag M (1997) Pentafuside (T-20), a novelinhibitor of HIV-1 fusion: pharmacokinetics in rodents, mon-keys and man. Antiviral Research 34:A36.

134. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M,Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, deBethune MP (2004) TMC125, a novel next-generation nonu-cleoside reverse transcriptase inhibitor active against nonnucle-oside reverse transcriptase inhibitor-resistant human


DNA_RNA 21/8/06 17:47 Page 164


Antiviral Chemistry & Chemotherapy 17.3 FFFF aaaa cccc tttt FFFF iiii llll eeeeimmunodeficiency virus type 1. Antimicrobial Agents andChemotherapy 48:4680–4686.

135. Baker C et al. Discovery of VX-175/GW433908, a novel,water-soluble prodrug of amprenavir. 39th InterscienceConference on Antimicrobial Agents and Chemotherapy, SanFrancisco, CA, USA, 1999. Abstract 916.

136. Furfine E et al. Preclinical development of GW433908/VX-175, the water-soluble phosphate prodrug of amprenavir. 39th39th Interscience Conference on Antimicrobial Agents andChemotherapy, San Francisco, CA, USA, 1999. Abstract 917.

137. Romines KR, Freeman GA, Schaller LT, Cowan JR, GonzalesSS, Tidwell JH, Andrews CW 3rd, Stammers DK, Hazen RJ,Ferris RG, Short SA, Chan JH & Boone LR (2006) Structure-activity relationship studies of novel benzophenones leading tothe discovery of a potent, next generation HIV nonnucleosidereverse transcriptase inhibitor. Journal of Medicinal Chemistry49:727–739.

138. Biron F, Lucht F, Peyramond D, Fresard A, Vallet T, Nugier F,Grange J, Malley S, Hamedi-Sangsari F & Vila J (1995) Anti-HIV activity of the combination of didanosine and hydroxyureain HIV-1-infected individuals. Journal of Acquired ImmuneDeficiency Syndromes and Human Retrovirology 10:36–40.

139. Johns DG & Gao WY (1998) Selective depletion of DNA pre-cursors: an evolving strategy for potentiation of dideoxynucleo-side activity against human immunodeficiency virus. BiochemicalPharmacology 55:1551–1556.

140. Kraus GA, Zhang WJ, Carpenter S & Wannemueler Y (1995)The synthesis and evaluation of hypericin analogues. Bioorganic& Medicinal Chemistry Letters 5:2633–2636.

141. Farnet CM, Wang B, Hansen M, Lipford JR, Zalkow L,Robinson WE Jr, Siegel J & Bushman F (1998) Humanimmunodeficiency virus type 1 cDNA integration: new aromat-ic hydroxylated inhibitors and studies of the inhibition mecha-nism. Antimicrobial Agents & Chemotherapy 42:2245–2253.

142. Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL,Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E, SardanaVV, Schlabach AJ, Graham PI, Condra JH, Gotlib L, HollowayMK, Lin J, Chen IW, Vastag K, Ostovic D, Anderson PS,Emini ES & Huff JR (1994). L-735,524: an orally bioavailablehuman immunodeficiency virus type 1 protease inhibitorProceedings of the National Academy of Sciences of the United Statesof America 91:4096–4100.

143. Hammer SM, Squires KE, Hughes MD, Grimes JM, DemeterLM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, DeytonLR, Chodakewitz JA & Fischl MA (1997) A controlled trial oftwo nucleoside analogues plus indinavir in persons with humanimmunodeficiency virus infection and CD4 cell counts of 200per cubic millimeter or less. AIDS Clinical Trials Group 320Study Team. New England Journal of Medicine 337:725–733.

144. Marquez VE, Tseng CK-H, Mitsuya S, Aoki JA, Kelley H,Ford JS Jr, Roth JS, Broder S, Johns DG & Driscoll JS (1990)Acid-stable 2′-fluoro purine dideoxynucleosides as active agentsagainst HIV. Journal of Medicinal Chemistry 33:978–985

145. Flanigan ME, Geiger SP, Ford H Jr, Baseler M, Adelsberger J,Davey RT Jr & Lane HC (1995). The human HIV/peripheralblood lymphocyte (PBL)–SCID mouse. Journal of Immunology154:6612–6623.

146. Graul A, Silvestre J & Castañer J (1998) Lodenosine. Drugs ofthe Future 23:1176–1189.

147. Carrillo A, Stewart KD, Sham HL, Norbeck DW, KohlbrennerWE, Leonard JM, Kempf DJ & Molla A (1998) In vitro selec-tion and characterization of human immunodeficiency virustype 1 variants with increased resistance to ABT-378, a novelprotease inhibitor. Journal of Virology 9:7532–7541.

148. Sham H, Kempf D, Molla A, Marsh K, Wideburg N, Chen C,Kati W, Kumar M, Korneyeva M, Vasavanonda S, McDonaldE, Saldivar A, Chernyavskiy T, Carillo A, Lyons N, Park C,Stewart K, Plattner J & Norbeck D. Design, synthesis and

biological properties of ABT-378, a highly potent HIV pro-tease inhibitor. Fourth Conference on Retroviruses andOpportunistic Infections Washington D.C., USA, 22–26 January1997. Abstract 14.

149. The CAESAR Coordinating Committee (1997) Randomisedtrial of addition of lamivudine or lamivudine plus loviride tozidovudine-containing regimens for patients with HIV-1 infec-tion: the CAESAR trial. Lancet 349:1413–1421.

150. Pauwels R, Andries K, Debyser Z, Van-Daele P, Schols D,Stoffels P, De Vreese K, Woestenboroghs R, Vandamme AM,Janssen CGM, Anne J, Cauwenbergh G, Desmyter J, HeykantsJ, Janssen MAC, De Clercq E & Janssen PAJ (1993) Potentand selective human immunodeficiency virus type 1 (HIV-1)inhibition by a series of alpha-anilinophenylacetamide deriva-tives targeted at HIV-1 reverse transcriptase. Proceedings of theNational Academy of Sciences of the United States of America90:1711–1715.

151. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M,Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R,Armour D, Price D, Stammen B, Wood A & Perros M (2005)Maraviroc (UK-427,857), a potent, orally bioavailable, andselective small-molecule inhibitor of chemokine receptor CCR5with broad-spectrum anti-human immunodeficiency virus type1 activity. Antimicrobial Agents and Chemotherapy 49:4721–4732.

152. Kang MS (1996) Uptake and metabolism of BuCast: a glyco-protein processing inhibitor and a potential anti-HIV drug.Glycobiology 6:209–216.

153. Taylor DL, Sunkara PS, Liu PS, Kang MS, Bowlin TL & TymsAS (1991) 6-O-Butanoyl castanospermine (MDL 28 574)inhibits glycoprotein processing and the growth of HIV. AIDS5:693–698.

154. Riech SH, Melnick M, Davies JF II, Appelt K, Lewis KK,Fuhry MA, Pino M, Trippe AJ, Nguyen D, Dawson H, WuBW, Musick L, Kosa M, Kalil D, Webber S, Gehlhaar DK,Andrada D & Shetty B (1995) Protein structure-baseddesign of potent orally available nonpeptide inhibitors ofhuman immunodeficiency virus protease. Proceedings of theNational Academy of Sciences of the United State of America92:3298–3302.

155. Shetty BV, Kosa MB, Khalil DA & Webber S (1996)Preclinical pharmacokinetics and distribution to tissue ofAG1343, an inhibitor of human immunodeficiency virus type 1protease. Antimicrobial Agents & Chemotherapy 40:30–34.

156. Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, SkougM, Wu JC, Shih CK, Eckner K, Hattox S, Adams J, RosenthalAS, Faarnes R, Eckner RJ, Koup RA & Sullivan JL (1990)Inhibition of HIV-1 replication by a non-nucleoside reversetranscriptase inhibitor. Science 250:1411–1413.

157. D’Aquila RT, Hughes MD, Johnson VA, Fischl MA,Sommadossi JP, Liou SH, Timpone J, Myers M, Basgoz N,Niu M, Hirsch MS (1996) Nevirapine, zidovudine anddidanosine compared with zidovudine and didanosine inpatients with HIV-1 infection – a randomized, double-blind,placebo-controlled trial. Annals of Internal Medicine124:1019–1030.

158. Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M,Matallana C, Castillo A, Zoumplis D, Martin DE, OrensteinJM, Allaway GP, Freed EO & Wild CT (2003) PA-457: apotent HIV inhibitor that disrupts core condensation by target-ing a late step in Gag processing. Proceedings of the NationalAcademy of Sciences of the United State of America100:13555–13560.

159. Vrang , Agreu C, Ekelof K, Engelshardt P, Hogsberg M,Noreen R, Oberg B, Rydergard C & Sahlberg C. Anti-HIVactivity of PETT-5 in vitro. 3th Conference on AntiviralResearch, San Diego, Calif., USA, 1998.

160. Otto MJ, Arasteh K, Schulbin H et al. Single and multiple dosepharmacokinetcs and safety of the nucleoside Racivir® in male

DNA_RNA 21/8/06 17:47 Page 165



volunteers. HIV DART 2002, Frontiers in Drug Developmentfor Antiretroviral Therapies, Naples, Florida, USA (2002)

161. Geleziunas R, Gallagher K, Zhang H, Bacheler L, Garber S,Wu J-T, Shi G, Otto MJ, Schinazi RF & Erickson-Viitanen S(2003) HIV-1 resistance profile of the novel nucleoside reversetranscriptase inhibitor beta-D-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (Reverset™). Antiviral Chemistry andChemotherapy 14:49–59.

162. Markowitz M, Hongnei MO, Kemp D, Dale J, Norbeck DW,Bhat TN, Erickson JW & Ho D (1995) Selection and analysisof human immunodeficiency virus type 1 variant with increasedresistance to ABT-538, a novel protease inhibitor. Journal ofVirology 69:701–706.

163. Cohen C, Revicki DA, Nabulsi A, Sarocco PW & Jiang P(1998) A randomized trial of the effect of ritonavir in main-taining quality of life in advanced HIV disease. Advanced HIVDisease Ritonavir Study Group. AIDS 12:1495–5502.

164. Roberts NA, Martin JA, Kinchington D, Broadhurst AV, CraigJC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A,Lambert RW, Merret JH, Mills JS, Parkes KEB, Redshaw S,Ritchie AJ, Taylor KL, Thomas GT & Machin PJ (1990)Rational design of peptide-based HIV proteinase inhibition.Science 248:358–361.

165. Perry CM & Noble S (1998) Saquinavir soft-gel capsule for-mulation. A review of its use in patients with HIV infection.Drugs 55:461–486.

166. Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J &Vandeputte M 1987) Both 2′,3′-dideoxythymidine and its2′,3′-unsaturated derivative (2′,3′-dideoxythymidinene) arepotent and selective inhibitors of human immunodeficiencyvirus replication in vitro. Biochemical and Biophysical ResearchCommunications 142:128–134.

167. Lin TS, Schinazi RF & Prusoff WH (1987) Potent and selec-tive in vitro activity of 3′-deoxythymidin-2′-ene(3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus.Biochemical Pharmacology 36:2713–2718.

168. Barney S, Guthrie K, Davis D, Newman L, Johnson MR &Lambert DM. A novel hybrid synthetic peptide inhibitor ofHIV-1, SIV and HIV-2 fusion and infection in vitro. 6thConference on Retroviruses and Opportunistic Infections, Chicago,IL, USA, 31 January–4 February 1999. Abstract 616.

169. Lambert DM, Zhou J, Medinas R, Guthrie K, Sista PR,Matthews T, Dusek A, Hopkins S & Bolognesi D (1999) HIV-1 isolates from patients treated with T-20 are sensitive to thesecond generation fusion inhibitor T1249. Antiviral Therapy 4(Suppl.1):8.

170. Turner SR, Strohbach JW, Tommasi RA, Aristoff PA, JohnsonPD, Skulnick HI, Dolak LA, Seest EP, Tomich PK, BohanonMJ, Horng MM, Lynn JC, Chong KT, Hinshaw RR,Watenpaugh KD, Janakiraman MN & Thaisrivongs S (1998)Tipranavir (PNU-140690): a potent, orally bioavailable non-peptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. Journal of Medicinal Chemistry41:3467–3476.

171. Thaisrivrongs S, Tomich PK, Watenpaugh KD, Chong KT,Howe WJ, Yang CP, Strohbach JW, Turner SR, McGrath JP,Bohanon MJ, Lynn JC, Mulichak AM, Spinelli PA, HinshawRR, Pagano PJ, Moon JB, Ruwart MJ, Wilkinson KF, RushBD, Zipp GL, Dalga RJ, Schwende FJ, Howard GM, PadburyGE, Toth LN, Zhao Z, Koeplinger KA, Kakuk TJ, Cole SL,Zaya RM, Piper RC & Jeffrey P (1994) Structure based designof HIV protease inhibitors: 4-hydroxy coumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors. Journal ofMedicinal Chemistry 37:3200–3204.

172. Pauwels R, Andries K, Debyser Z, Kukla M, Schols D, BreslinH, Woestenborghs R, Desmyter J, Janssen MAC, De Clercq E

& Janssen PAJ (1994) New [4,5,1-JK][1,4]benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors ofhuman immunodeficiency virus type 1 and are synergistic with2′,3′-dideoxynucleoside analogues. Antimicrobial Agents &Chemotherapy 38:2863–2870.

173. Zhang H, Vrang L, Backbro K, Lind P, Sahlberg C, Unge T &Öberg B (1995). Inhibition of human immunodeficiency virustype 1 wild-type and mutant reverse transcriptases by thephenyl ethyl thiazolyl thiourea derivatives Trovirdine andMSG-127. Antiviral Research 28:331–342.

174. De Clercq E (2004) Non-nucleoside reverse transcriptaseinhibitors (NNRTIs): past, present and future. Chemistry &Biodiversity 1:44–64.

175. Ahgren C, Backro K, Bell FW, Cantrell AS, Clemens M,Colacino JM, Deeter JB, Engelhardt JA, Hogberg M, JaskunasSR, Johansson NG, Jordan CL, Kasher JS, Kinnick MD, Lind P,Lopez C, Morin JM Jr, Muesign MA, Noreen R, Oberg B,Paget CJ, Palkowitz JA, Parrish CA, Pranc R, Rippy MK,Rydergard C, Sahlberg C, Swanson S, Ternansky RJ, Unge T,Vasileff RT, Vrang L, West SJ, Zhang H & Zhou X-X (1995)The PETT series, a new class of potent non-nucleosideinhibitors of human immunodeficiency virus type 1 reverse tran-scriptase. Antimicrobial Agents & Chemotherapy 39:1329–1335.

176. Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, GonsiorekW, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y, Tagat JR,Cox K, Priestley T, Sorota S, Huang W, Hirsch M, Reyes GR& Baroudy BM (2005) Discovery and characterization ofvicriviroc (SCH 417690), a CCR5 antagonist with potent activ-ity against human immunodeficiency virus type 1. AntimicrobialAgents and Chemotherapy 49:4911–4919.

177. Mitsuya H & Broder S (1986) Inhibition of the in vitro infec-tivity and cytopathic effect of human T-lymphotropic virustype III/lymphadenopathy-associated virus (HTLV-III/LAV)by 2′,3′-dideoxynucleosides. Proceedings of the National Academyof Sciences of the United States of America 83:193–1915.

178. Moyle GJ & Gazzard BG (1998) Finding a role for zalcitabinein the HAART era. Antiviral Therapy 3:125–137.

179. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, NussinoffLehrman S, Gallo RC, Bolognesi D, Barry DW & Broder S(1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviralagent that inhibits the infectivity and cytopathic effect of humanT-lymphotropic virus type III/lymphadenopathy-associatedvirus in vitro. Proceedings of the National Academy of Sciences of theUnited States of America 82:7096–7100.

180. Ioannidis JPA, Cappelleri JC, Lau J, Skolnik PR, Melville B,Chalmers TC & Sacks HS (1995). Early or deferred zidovu-dine therapy in HIV-infected patients without an AIDS-defin-ing illness – a meta analysis. Annals of Internal Medicine122:856–866.

181. Westby M & van der Ryst (2005) CCR5 antagonists: host-tar-geted antivirals for the treatment of HIV infection. AntiviralChemistry & Chemotherapy 16:339–354.

182. Vere Hodge A (2003) Telbivudine/torcitabine (Idenix.Novartis).Current Opinion in Investigational Drugs 5: 232–241.

183. Bryant ML, Bridges EG, Placidi L, Faraj A, Loi G, Pierra C,Dukhan D, Gosselin G, Imbach J-L, Hernandez B, JuodawlkisA, Tennant B, Korba B, Cote P, Marion P, Cretton-Scott E &Schinazi RF, and Sommadossi J-P (2001) Antiviral L-nucleo-sides specific for hepatitis B virus infection. AntimicrobialAgents and Chemotherapy 45: 229–235.

184. Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, HanS, Poynard T, Myers M, Chao G, Lloyd D & Brown NA(2005) A 1-year trial of telbivudine, lamivudine, and the combi-nation in patients with hepatitis B e antigen-positive chronichepatitis B. Gastroenterology 129: 528–536.


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