266
Views
122
CrossRef citations to date
0
Altmetric
Review

Emerging anti-HIV drugs

Pages 241-274 | Published online: 10 May 2005

Bibliography

  • DE CLERCQ E: Suramin : a potent inhibitor of the reverse transcriptase of RNA tumor viruses. Cancer Lett. (1979) 8:9–22.
  • MITSUYA H, POPOVIC M, YARCHOAN R, MATSUSHITA S, GALLO RC, BRODER S: Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science (1984) 226:172–174.
  • •First demonstration of in vitro activity of an antiviral agent.
  • BRODER S, YARCHOAN R, COLLINS JM et al.: Effects of suramin on HTL V-III/LAV infection presenting as Kaposi's sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo. Lancet (1985) 2:627–630.
  • •First demonstration of in vitro efficacy of an anti-HIV agent.
  • MITSUYA H, WEINHOLD KJ, FURMAN PA et al.: 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus Type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci. USA (1985) 82:7096–7100.
  • •Demonstration of in vitro activity of compound (zidovudine) that was the first to be licensed for clinical use in the treatment of AIDS.
  • MITSUYA H, BRODER S: Inhibition of the in vitro infectivity and cytopathic effect of human T-Iymphotropic virus Type III/ lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc. Natl. Acad. Sci. USA (1986) 83:1911–1915.
  • BABA M, PAUWELS R, HERDEWIJN P, DE CLERCQ E, DESMYTER J, VAN DE PUTTE M: Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem. Biophys. Res. Commun. (1987) 142:128–134.
  • YENI PG, HAMMER SM, HIRSCH MS et al.: Treatment for adult HIV infection. 2004 Recommendations of the International AIDS Society-USA Panel. J. Am. Med. Assoc. (2004) 292:251–265.
  • BLANKSON JN, PERSAUD D, SILICIANO RF: The challenge of viral reservoirs in HIV-1 infection. Ann. Rev. Med. (2002) 53: 557–593.
  • DE CLERCQ E: Antiviral drugs in current clinical use. J. Clin. Virol (2004) 30:115–133.
  • DE CLERCQ E: Strategies in the design of antiviral drugs. Nature Rev. Drug Discov. (2002) 1:13–25.
  • DE CLERCQ E: Antivirals and antiviral strategies. Nature Rev. Microbiol (2004) 2:704–720.
  • MATTHEWS T, SALGO M, GREENBERG M, CHUNG J, DEMASI R, BOLOGNESI D: Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nature Rev. Drug Discov. (2004) 3:215–225.
  • ••Provides a full account on the discovery and development ofenfuvirtide, the first viral entry inhibitor to enter the market.
  • COOPER DA, LANGE JM: Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. Lancet Infect. Dis. (2004) 4:426–436.
  • JOHNSON VA, BRUN-VEZINET F, CLOTET B et al.: Update of the drug resistance mutations in HIV-1: 2004. Top. HIV Med. (2004) 12:119–124.
  • TURNER D, SCHAPIRO JM, BRENNER BG, WAINBERG MA: The influence of protease inhibitor resistance profiles on selection of HIV therapy in treatment-naïve patients. Antiviral Ther. (2004) 9:301–314.
  • POVEDA E, RODES B, LABERNARDIERE J-L et al.: Evolution of genotypic and phenotypic resistance to enfuvirtide in HIV-infected patients experiencing prolonged virologic failure. J. Med. Virol (2004) 74:21–28.
  • GREENBERG ML, CAMMACK N: Resistance to enfuvirtide, the first HIV fusion inhibitor. J. Antimicrob. Chemother. (2004) 54:333–340.
  • MILLER MD, HAZUDA DJ: HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. Drug Resistance Updates (2004) 7:89–95.
  • HEIL ML, DECKER JM, SFAKIANOS JN et al.: Determinants of human immunodeficiency virus Type 1 baseline susceptibility to the fusion inhibitors enfuvirtide and T-649 reside outside the peptide interaction site. J. Virol (2004) 78:7582–7589.
  • GALLANT JE, STASZEWSKI S, POZNIAK AL et al.: Efficacy and safety of tenofovir DF versus stavudine in combination therapy in antiretroviral-naive patients. A 3-year randomized trial. J. Am. Med. Assoc. (2004) 292:191–201.
  • •Comparative clinical study demonstrating that the TDF arm, although comparable in antiviral efficacy, gives fewer adverse effects than the stavudine arm.
  • POZNIAK A, GALLANT J, STASZEWSKI S et al.: Long-term efficacy and safety of tenofovir DF (TDF): a 144 week comparison versus stavudine (d4T) in antiretroviral-naïve patients. 7th International Congress on Drug Therapy in HIV Infiction. Glasgow, UK, (2004).
  • SAAG MS, CAHN P, RAFFI F et al.: Efficacy and safety of emtricitabine versus stavudine in combination therapy in antiretroviral-naïve patients. A randomized trial. J. Am. Med. Assoc. (2004) 292:180–190.
  • •Comparative clinical study indicating that the emtricitabine arm has a better efficacy/ safety profile than the stavudine arm.
  • GAZZARD B, DEJESUS E, CAMPO R et al.: The combination of tenofovir DF (TDF), emtricitabine (FTC) and efavirenz (EFV) has significantly greater response versus fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral naïve patients: a 24 week preliminary analysis. 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC, USA, (2004).
  • •Preliminary analysis of 24-week comparative clinical study points to the superiority of the combination TDF/ emtricitabine over the combination zidovudine/lamivudine.
  • ARRIBAS JR, DEJESUS E, CAMPO R et al.: The combination of tenofovir DF (TDF), emtricitabine (FTC) and efavirenz (EFV) has significantly greater response versus fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral naïve patients: a 24 week preliminary analysis. 7th International Congress on Drug Therapy in HIV Infection. Glasgow, UK, (2004).
  • •As for [23].
  • LALEZARI JP, DEJESUS E, NORTHFELT DW et al.: A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antiviral Ther. (2003) 8:279–287.
  • ZHANG X, LALEZARI JP, BADLEY AD et al.: Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus Type 1-infected patients. Clin. Pharmacol Ther. (2004) 75:558–568.
  • CORBETT AH, ERON JJ, FISCUS SA,REZK NL, KASHUBA AD: The pharmacokinetics, safety, and initial virologic response of a triple-protease inhibitor salvage regimen containing amprenavir, saquinavir, and ritonavir. Acquir. Immune Defic. Syndr. (2004) 36:921–928.
  • MARTINEZ E, ARNAIZ JA, PODZAMCZER D: Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl. J. Med. (2003) 349:1036–1046.
  • GERSTOFT J, KIRK O, OBEL N et al:Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine. AIDS (2003) 17:2045–2052.
  • HOOGEWERF M, REGEZ RM, SCHOUTEN WE, WEIGEL HM, FRISSEN PH, BRINKMAN K: Change to abacavir-lamivudine-tenofovir combination treatment in patiens with HIV-1 who had complete virological suppression. Lancet (2003) 362:1979–1980.
  • PEYRIERE H, GUILLEMIN V, LOTTHE A et al.: Reasons for early abacavir discontinuation in HIV-infected patients. Ann. Pharmacother. (2003) 37:1392–1397.
  • ABURET A-M, PIKETTY C, CHAZALLON C et al.: Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. (2004) 48:2091–2096.
  • VERMEIRE K, ZHANG Y, PRINCEN K et al.: CADA inhibits immunoeficiency virus and human herpesvirus 7 replication by down-modulation of the cellular CD4 receptor. Virology (2002) 302:342–353.
  • VERMEIRE K, BELL TW, CHOI H-J et al: The anti-HIV potency of cyclotriazaisulfonamide analogs is directly correlated with their ability to down-modulate the CD4 receptor. Mol. PharmacoL (2003) 63:203–210.
  • VERMEIRE K, VAN LAETHEM K, VAN DAMME A-M, BELL T, DE CLERCQ E, SCHOLS D: Resistance profile of human immunodeficiency virus to CADA, a novel HIV inhibitor that targets the cellular CD4 receptor. Abstracts of the 18th International Conference on Antiviral Research. Barcelona, Spain (2005).
  • VERMEIRE K, PRINCEN K, HATSE S et al.: CADA, a novel CD4-targeted HIV inhibitor, is synergistic with various anti-HIV drugs in vitro. AIDS (2004) 18:2115–2125.
  • BALZARINI J, HATSE S, VERMEIRE K et al.: Mannose-specific plant lectins from the Amaryllidaceae family qualify as efficient microbicides for prevention of human immunodeficiency virus infection. Antimicrob. Agents Chemother. (2004) 48:3858–3870.
  • BALZARINI J, VAN LAETHEM K, HATSE S et al.: Profile of resistance of human immunodeficiency virus to mannose-specific plant lectins. J. ViroL (2004) 78:10617–10627.
  • BOYD MR, GUSTAFSON KR, MCMAHON JB et al.: Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob. Agents Chemother. (1997) 41:1521–1530.
  • MORI T, BOYD MR: Cyanovirin-N, a potent human immunodeficiency virus-inactivating protein, blocks both CD4-dependent and CD4-independent binding of soluble gp120 (sgp120) to target cells, inhibits sCD4-induced binding of sgp120 to cell-associated CXCR4, and dissociates bound sgp120 from target cells. Antimicrob. Agents Chemother. (2001) 45:664–672.
  • WANG T, ZHANG Z, WALLACE OB: Discovery of 4-benzoy1-1-R4-methoxy-1H- pyrrolopyridin-3-y1) oxoacetyll -2-(R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. J. Med. Chem. (2003) 46:4236–4239.
  • GUO Q, HO H-T, DICKER I et al.: Biochemical and genetic characterizations of a novel human immunodeficiency virus Type 1 inhibitor that blocks gp120-CD4 interactions. J. Virol (2003) 77:10528–10536.
  • MADANI N, PERDIGOTO AL, SRINIVASAN K et al.: Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155 Virol (2004) 78:3742–3752.
  • LIN P-F, BLAIR W, WANG T et al.: A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc. Natl. Acad. Sci. USA (2003) 100:11013–11018.
  • COLONNO R, HO H, ZHOU N et al: BMS-488043: a novel, small-molecule HIV-1 attachment inhibitor. 13th International Symposium on HIV & Emerging Infectious Diseases. Toulon, France (2004).
  • COLONNO R, HO H, ZHOU N et al: HIV attachment inhibitors - a novel class of antiretrovirals in clinical development. HIV DART 2004 - Frontiers in Drug Development for Antiremoviral Therapies. Montego Bay, Jamaica (2004).
  • DE CLERCQ E: The bicyclam AMD3100 story. Nature Rev. Drug Discov. (2003) 2:581–587.
  • ••Provides an account of how a compoundoriginally discovered as an anti-HIV agent is now further developed for mobilisation and transplantation of stem cells.
  • HENDRDC CW, FLEXNER C, MACFARLAND RT et al: Pharmacokinetics and safety ofAMD-3100, a novel antagonist of the CXCR4-chemokine receptor, in human volunteers. Antimicrob. Agents Chemother. (2000) 44:1667–1673.
  • SCHOLS D, CLAES S, DE CLERCQ E et al.: AMD-3100, a CXCR4 antagonist, reduced HIV viral load and X4 virus levels in humans. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • SCHOLS D, CLAES S, HATSE S et al.: Anti-HIV activity profile of AMD070, an orally bioavailable CXCR4 antagonist. 16th International Conference on Antiviral Research. Savannah, Georgia, USA (2003).
  • ICHIYAMA K, YOKOYAMA-KUMAKURA S, TANAKA Y et al: A duodenally absorbable OCC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA (2003) 100:4185–4190.
  • PRINCEN K, HATSE S, VERMEIRE K et al.: Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. J. Virol. (2004) 78:12996–13006.
  • •First report on a dual CCR5/CXCR4 antagonist.
  • BABA M, NISHIMURA O, KANZAKI N et al: A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA (1999) 96:5698–5703.
  • DRAGIC T, TRKOLA A, THOMPSON DA et al: A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl Acad. Sci. USA (2000) 97:5639–5644.
  • IIZAWAY, KANZAKI N, TAKASHIMA K et al: Anti-HIV-1 activity of TAK-220, a small molecule CCR5 antagonist. 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA (2003).
  • STRIZKI JM, XU S, WAGNER NE et al.:SCH-C (SCH 351125), an orally bioavaible, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc. Natl. Acad. Sci. USA (2001) 98:12718–12723.
  • REYNES J, ROUZIER R, KANOUNI T et al.: SCH C: safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • DUNKLE LM: CCR5 receptor antagonist SCH-417690: a new class of potent HIV Therapies. HIV DART 2004 Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004)
  • MAEDA K, YOSHIMURA K, SHIBAYAMA S et al.: Novel low molecular weight spirodiketopiperazine derivatives
  • MAEDA K, NAKATA H, OGATA H et al: GW873140 potent against HIV-1, its CCR5 binding profile and synergy with other anti-HIV-1 agents. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • MAEDA K, NAKATA H, KOH Y et al.: Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/ CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus Type 1 in vitro.
  • DORR P, MACARTNEY M, RICKETT G et al: UK-427,857, a novel small molecule HIV entry inhibitor is a specific antagonist of the chemokine receptor CCR5. 10th Conference on Retroviruses and Opportunistic Infections. Boston, Massachusetts, USA
  • HITCHCOCK CA: The discovery and exploratory development of UL-427,857: a novel CCR5 antagonist for the treatment of HIV 13th International Symposium on HIV & Emerging Infectious Diseases. Toulon, France (2004).
  • MAYER HB: UK-427,857: a novel small molecule CCR5 receptor antagonist. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • STODDART CA, MORENO ME, LINQUIST-STEPPS VD et at.: Antiviral activity of 2'-deoxy-3'-oxa-4'-thiocytidine (BCH-10652) against lamivudine-resistant human immunodeficiency virus Type 1 in SCID-hu Thy/Liv mice. Antimicrob. Agents Chemother. (2000) 44:783–786.
  • OTTO MJ, ARASTEH K, SCHULBIN H et al.: Single and multiple dose pharmacokinetics and safety of the nucleoside Racivir® in male volunteers. HIV DART 2002, Frontiers in Drug Development for Antiretroviral Therapies. Naples, Florida, USA (2002).
  • MANSOUR TS, JIN H, WANG W et al: Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5-fluoro analogues in vitro. J. Med. Chem. (1995) 38:1–4.
  • BETHELL R: Pharmacological evaluationof SPD754, a new NRTI. 13th International Symposium on HIV d'-• Emerging Infectious Diseases. Toulon, France (2004).
  • BALZARINI J, PAUWELS R, HERDEWIJN P et al: Potent and selective anti-HTLV-III/LAV activity of 2',3'-dideoxycyticlinene, the 2',3'-unsaturated derivative of 2',3'-dideoxycytidine. Biochem. Biophys. Res. Commun. (1986) 140:735–742.
  • SCHINAZI RF, MELLORS J, BAZMI H et al.: DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants. Antimicrob. Agents Chemother. (2002) 46:1394–1401.
  • GELEZIUNAS R, GALLAGHER K, ZHANG H et al.: HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor 13-0-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (ReversetTm). Antiviral Chem. Chemother. (2003) 14:49–59
  • PHY R: NRTIs : recent advances and how to use them judiciously. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • FURMAN PA, JEFFREY J, KIEFER LL et al.: Mechanism of action of 1-13-0-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus Type 1 inhibitor 1-13-0-dioxolane guanosine. Antimicrob. Agents Chemother. (2001) 45:158–165.
  • JEFFREY JL, FENG JY QI CC, ANDERSON KS, FURMAN Pk Dioxolane guanosine 5'-triphosphate, an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Biol. Chem. (2003) 278:18971–18979.
  • KEWN S, WANG LH, HOGGARD PG et al.: Enzymatic assay for measurement of intracellular DXG triphosphate concentrations in peripheral blood mononuclear cells from human immunodeficiency virus Type 1-infected patients. Antimicrob. Agents Chemother. (2003) 47:255–261.
  • PAINTER GR, ST CLAIRE R, FENG J, BORROTO-ESODAK: Anabolic profile of the dioxolane nucleoside analogue DXG in human PBMC; reversal of resistance by boosting 5'-triphosphate levels. 15th International Conference on Antiviral Research. Prague, Czech Republic (2002).
  • MEWSHAW JP, MYRICK FT, WAKEFIELD DACS et al: Dioxolane guanosine, the active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of drug-resistant HIV-1 isolates from patients for whom standard nucleoside therapy fails. J. Acquir. Immune Defic. Syndr. (2002) 29:11–20.
  • CHU CK, YADAV V, RAPP KL, DETORIO M, SCHINAZI RF: 1-(13-0-Dioxolane)thymine is active against a variety of clinically relevant NRTI drug resistant HIV-1 strains. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • DE CLERCQ E: The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res. (1998) 38:153–179.
  • DE CLERCQ E: Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present and future. Chemistry & Biodiversity (2004) 1:44–64.
  • BORKOW G, BARNARD J, NGUYEN TM et al: Chemical barriers to human immunodeficiency virus Type 1 (HIV-1) infection: retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoside inhibitor of HIV-1 reverse transcriptase Wro. (1997) 71:3023–3030.
  • BALZARINI J, NAESENS L, VERBEKEN E et al.: Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent. AIDS (1998) 12:1129–1138.
  • VAN HERREWEGE Y, VANHAM G, MICHIELS J et al: A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides. Antimicrob. Agents Chemother. (2004) 48:3684–3689.
  • REN J, NICHOLS C, BIRD LE et al.: Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse trancriptase involves extensive main chain hydrogen bonding. J. Biol. Chem. (2000) 275:14316–14320.
  • ANDRIES K, AZIJN H, THIELEMANS T et al.: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus Type 1. Antimicrob. Agents Chemother. (2004) 48:4680–4686.
  • GAZZARD B, POZNIAK A, ARASTEH K et al.: TMC125, a next-generation NNRTI, demonstrates high potency after 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • SANKATSING S, WEVERLING G, VAN T, KLOOSTER G, PRINS J, LANGE J: TMC125 monotherapy for 1 week results in a similar initial rate of decline of HIV-1 RNA as therapy with a 5-drug regimen. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • GAZZARD BG, POZNIAK AL, ROSENBAUM W et al.: An open-label assessment of TMC 125 - a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS (2003) 17:F49–F54.
  • SARAFIANOS SG, DAS K, HUGHES SH, ARNOLD E: Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. Curr. Opin Struct. Biol. (2004) 14:716–730.
  • DAS K, LEWI PJ, HUGHES SH, ARNOLD E: Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Frog. Biophys. Md. Biol. (2005) 88:209–231.
  • •The behaviour of an NNRTI in the reverse transcriptase binding (pocket') site, or the art of 'wiggling' and 'jiggling'.
  • JANSSEN PA, LEWI PJ, ARNOLD E et al.: In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4- fl4-4[4-R1E)-2- cyanoethenyll -2,6-dimethylphenyllaminol-2-pyrimidinyll aminolbenzonitrile (R278474, rilpivirine). J. Med. Chem. (2005) 48:1901–1909.
  • ••Fascinating story on how a long-termmultidisciplinary approach over a period of 17 years led to the identification of the most potent anti-HIV agent ever described: a tribute to the late Dr Paul Janssen.
  • PAUWELS R: New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Curr. Opin. Pharmacol (2004) 4:437–446.
  • HAZUDA DJ, FELOCK P, WITMER M et al.: Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science (2000) 287:646–650.
  • PLUYMERS W, PAIS G, VAN MAELE B et al.: Inhibition of human immunodeficiency virus Type 1 integration by diketo derivatives. Antimicrob. Agents Chemother. (2002) 46:3292–3297.
  • FIKKERT V VAN MAELE B, VERCAMMEN J et al.: Development of resistance against diketo derivatives of human immunodeficiency virus Type 1 by progressive accumulation of integrase mutations. J. Virol (2003) 77:11459–11470.
  • HAZUDA DJ, ANTHONY NJ, GOMEZ RP et al.: A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl Acad. Sci. USA (2004) 101:11233–11238.
  • HAZUDA DJ, YOUNG SD, GUARE JP et al.: Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science (2004) 305:528–532.
  • ••First demonstration of in vivo antiviral efficacy of an HIV integrase inhibitor.
  • YOSHINAGA T, SATO A, FUJISHITA T, FUJIWARA T: S-1360: in vitro activity of a new HIV-1 integrase inhibitor in clinical development. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • GROBLER JA, STILLMOCK, HUB et al.: Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl Acad. Sci. USA (2002) 99:6661–6666.
  • PANNECOUQUE C, PLUYMERS W, VAN MAELE B et al.: New class of HIV integrase inhibitors that block viral replication in cell culture. Cuff. Biol. (2002) 12:1169–1177.
  • YOSHIMURA K, KATO R, KAVLICK MF et al.: A potent human immunodeficiency virus Type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A285) mutation in the protease active site. J. ViroL (2002) 76:1349–1358.
  • DE BETHUNE M, WIGERINCK P, JONCKHEERE H et al.: TMC 114, a highly potent protease inhibitor (PI) with an excellent profile against HIV variants highly resistant to current Pis. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Chicago, Illinois, USA (2001).
  • VAN DER GEEST R, VAN DER, SANDT I, GILLE D, GROEN K, TRITSMANS L, STOFFELS P: Safety, tolerability and pharmacokinetics of escalating singe oral doses of TMC 114, a novel protease inhibitor (PI) highly active against HIV-1 variants resistant to other Pis. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Chicago, Illinois, USA (2001).
  • LEFEBVRE E: TMC114: a new PI. 13th International Symposium on HIV & Emerging Infectious Diseases. Toulon, France (2004).
  • POPPE SM, SLADE DE, CHONG KT et al.: Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor. Antimicrob. Agents Chemother. (1997) 41:1058–1063.
  • TURNER SR, STROHBACH JW, TOMMASI RA et al.: Tipranavir (PNU-140690): a potent, orally bioavaible nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J. Med. Chem. (1998) 41:3467–3476.
  • LARDER BA, HERTOGS K, BLOOR S et al.: Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS (2000) 14:1943–1948.
  • RUSCONI S, LA SETA CATAMANCIO S, CITTERIO P et al.: Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus Type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob. Agents Chemother (2000)44:1328-1332.
  • MCCALLISTER S, SABO J, GALITZ L, MAYERS D: An open-label steady state investigation of the pharmacokinetics (PK) of tipranavir (TPV) and ritonavir (RTV) and their effects on cytochrome P450 (3A4) activity in normal health volunteers (BI 1182.5). 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • SCHWARTZ R, KAZANJIAN P, SLATER L et al.: Resistance to tipranavir is uncommon in a randomized trial of tipranavir/ritonavir (TPV/RTV) in multiple PI-failure patients (BI 1182.2). 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, USA (2002).
  • LI F, GOILA-GAUR R, SALZWEDEL K et al.: PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc. Natl Acad. Sci. USA (2003) 100:13555–13560.
  • •New original approach based on targeting the viral capsid.
  • MARTIN DE: Maturation inhibition: a new class of potent HIV inhibitors that disrupts core condensation by targeting a late step in Gag processing. HIV DART 2004- Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • ZHOU J, YUAN X, DISMUKE D et al: Small-molecule inhibition of human immunodeficiency virus Type 1 replication by specific targeting of the final step of virion maturation. J. Wrol. (2004) 78:922–929.
  • ANDERSSON E, HORAL P, JEJCIC A et al.: Glycine-amide is an active metabolite of the antiretroviral tripeptide glycyl-prolyl-glycine-amide. Antimicrob. Agents Chemother. (2005) 49:40–44.
  • VAHLNE A, ANDERSSON E, SVENNERHOLM B et al: AlphaHGA: a new antiviral substance against HIV affecting capsid assembly. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • ANDERSSON E, HORAL P, VAHLNE A, SVENNERHOLM B: No cross-resistance or selection of HIV-1 resistant mutants in vitro to the antiretroviral tripeptide glycyl-prolyl-glycine-amide. Antiviral Res. (2004) 61:119–124.
  • KURITZKES DR: Future paradigm shifts in first-line therapy? HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • VELLA JE, MYRICK F, RAY AS, MILLER MD, BORROTO-ESODA K: In vitro evaluation of the anti-HIV activity and metabolic interactions of emtricitabine and tenofovir. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • ERICKSON J, EISSENSTAT M, SILVA A, GULNIK S, AFONINA E, LUDTKE D: HIV protease inhibitors: what is left to do so? HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • MCCALLISTER S, KOHLBRENNER VM, VILLACIAN J, MUKWAYA G, NEUBACHER D, MAYERS D: Twenty-four week combined analysis of the tipranavir (TPV) RESIST studies of 1483 treatment-experienced patients given either tipranavir/ritonavir (TPV/r) or an optimized standard of care regimen using one of four ritonavir-boosted comparator PIs (CPI/r). HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • TRUE AL, ZHANG Y, CHIU YY et al.: Needle-free administration of enfuvirtide with BiojectorTm 2000 (B2000) demonstrates pharmacokinetic bioequivalence to standard needle administration. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • KATLAMA C, CANESTRI A, QUAGARI Z et al.: Foscarnet used in salvage therapy of multidrug resistant HIV-1 infected patients. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • DEEKS SG: Pathogenesis of drug-resistant HIV: implications for treatment strategies. HIV DART 2004 - Frontiers in Drug Development for Antiretroviral Therapies. Montego Bay, Jamaica (2004).
  • PAUWELS R, DE CLERCQ E: Development of vaginal microbicides for the prevention of heterosexual transmission of HIV. J. Acquir. Immune Defic. Syndr. Human Retrovirol. (1996) 11: 211–221.
  • NEYTS J, DE CLERCQ E: Effect of polyanionic compounds on intracutaneous and intravaginal herpesvirus infection in mice: impact on the search for vaginal microbicides with anti-HIV activity. Acquir. Immune Defic. Syndr. Hum. Retrovirol. (1995) 10:8–12.
  • DEZZUTTI CS, JAMES VN, RAMOS A et al: In vitro comparison of topical microbicides for prevention of human immunodeficiency virus Type 1 transmission. Antimicrob. Agents Chemother. (2004) 48:3834-3844. Affiliation

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.