Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The design of drugs for HIV and HCV

Nature Reviews Drug Discovery volume 6, pages 1001–1018 (2007)Cite this article

Key Points

  • Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infect 40 million and 170 million people worldwide, respectively. There is no vaccine for either virus, but drug development is progressing at a rapid pace. Here we review aspects of the medicinal chemistry and history of drug design for HIV and HCV, targeting similar stages in the viral life cycle.

  • At present, 24 drugs have been formally approved for the treatment of HIV infections. They belong to 7 different classes: NRTIs (nucleoside reverse transcriptase inhibitors), NtRTIs (nucleotide reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), protease inhibitors, fusion inhibitors, CRIs (co-receptor inhibitors) and integrase inhibitors (INIs).

  • Current strategies for combating HCV are remarkably reminiscent of those previously pursued for affronting HIV infections. Drug classes that are being developed include inhibitors of the viral protease (aspartyl protease for HIV; serine protease for HCV) and inhibitors of the viral polymerase (RNA-dependent DNA polymerase (reverse transcriptase) for HIV; RNA-dependent RNA polymerase (RNA replicase) for HCV)

  • Cyclophilin inhibitors (such as cyclosporin A analogues) have been found to inhibit both HIV and HCV replication.

  • The ultimate goal in the therapy of any virus is the elimination of the virus from the organism. For HIV, a definitive eradication may not be achievable. For HCV, however, the prospect of a true cure seems much more realistic. As for HIV, any chemotherapeutic approaches to curtail HCV infections are likely to be based on the combination of several drugs interacting with different targets within the viral replicative cycle.

Abstract

Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antiviral drugs, and future treatment strategies for chronic HCV might involve combination regimens that are analogous to those currently used for HIV. By considering the drug targets in the different stages of the life cycle of these two viruses, this article presents aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV, and highlights general lessons learned from anti-HIV-drug design that could be applied to HCV.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Simplified flow charts of the life cycles of human immunodeficiency virus (HIV) and hepatitis C virus (HCV).
Figure 2: Human immunodeficiency virus (HIV) reverse transcriptase.
Figure 3: Nucleoside and non-nucleoside reverse transcriptase inhibitors.
Figure 4: NS5B RNA replicase inhibitors: part 1.
Figure 5: NS5B RNA replicase inhibitors: part 2.
Figure 6: Human immunodeficiency virus (Hiv) protease inhibitors.
Figure 7: NS3 hepatitis C virus (HCV) protease inhibitors.
Figure 8: Inhibiting human immunodeficiency virus (HIV) fusion.
Figure 9: Human immunodeficency virus (HIV) co-receptor antagonists.
Figure 10: Human immunodeficiency virus (HIV) integrase inhibitors.
Figure 11: Human immunodeficiency virus (HIV) maturation inhibition.

Similar content being viewed by others

References

  1. Mitsuya, H. 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 82, 7096–7100 (1985). First description of 3′-azido-3′-deoxythymidine (AZT), later to be licensed as the first antiviral drug for the treatment of HIV infections (AIDS) in 1987.

    CAS  PubMed  Google Scholar 

  2. Coffin, J. et al. What to call the AIDS virus? Nature 321, 10 (1986).

    CAS  PubMed  Google Scholar 

  3. Popovic, M. et al. Isolation and transmission of human retrovirus (human T-cell leukemia virus). Science 219, 856–859 (1983).

    CAS  PubMed  Google Scholar 

  4. Barré-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).

    PubMed  Google Scholar 

  5. Chermann, J. C. et al. Isolation of a new retrovirus in a patient at risk for acquired immunodeficiency syndrome. Antibiot. Chemother. 32, 48–53 (1983).

    CAS  PubMed  Google Scholar 

  6. De Clercq, E. Anti-HIV drugs. Verh. K. Acad. Geneesk. Belg. 64, 81–104 (2007).

    Google Scholar 

  7. Fried, M. W. et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347, 975–982 (2002).

    CAS  PubMed  Google Scholar 

  8. Janssen, P. A. J. et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2, 6-dimethylphenyl]amino]-2- pyrimi-dinyl]amino]benzonitrile (R278474, rilpivirine). J. Med. Chem. 48, 1901–1909 (2005). Rilpivirine, now also known as TMC 278, was announced as a highly promising non-nucleoside reverse transcriptase inhibitor (NNRTI) by Dr. Paul Janssen's co-workers, after his untimely death.

    CAS  PubMed  Google Scholar 

  9. Tantillo, C. et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J. Mol. Biol. 243, 369–387 (1994).

    CAS  PubMed  Google Scholar 

  10. Pauwels R. New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Curr. Opin. Pharmacol. 4, 437–446 (2004).

    CAS  PubMed  Google Scholar 

  11. De Clercq, E. Strategies in the design of antiviral drugs. Nature Rev. Drug Discov. 1, 13–25 (2002).

    CAS  Google Scholar 

  12. De Clercq, E. & Holý, A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nature Rev. Drug Discov. 4, 928–940 (2005). Description of the impact of the acyclic nucleoside analogues as antiviral agents for the treatment of a wide variety of DNA virus and retrovirus infections, including HIV and HBV infections.

    CAS  Google Scholar 

  13. De Clercq, E. Emerging anti-HIV drugs. Expert Opin. Emerging Drugs 10, 241–274 (2005).

    CAS  Google Scholar 

  14. Hurwitz, S. J., Otto, M. J. & Schinazi, R. F. Comparative pharmacokinetics of Racivir, (±)-β-2′, 3′-dideoxy-5-fluoro-3′-thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans. Antiviral Chem. Chemother. 16, 117–127 (2005).

    CAS  Google Scholar 

  15. Herzmann, C. et al. Safety, pharmacokinetics, and efficacy of (±)-β-2′, 3′-dideoxy-5-fluoro-3′-thiacytidine with efavirenz and stavudine in antiretroviral-naïve human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 49, 2828–2833 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cahn, P. et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 20, 1261–1268 (2006).

    CAS  PubMed  Google Scholar 

  17. Frankel, F. A., Coutsinos, D., Xu, H. & Wainberg, M. A. Kinetics of inhibition of HIV type 1 reverse transcriptase-bearing NRTI-associated mutations by apricitabine triphosphate. Antiviral Chem. Chemother. 18, 93–101 (2007).

    CAS  Google Scholar 

  18. Wainberg, M. A., Cahn, P., Bethell, R. C., Sawyer, J. & Cox, S. Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection. Antiviral Chem. Chemother. 18, 61–70 (2007).

    CAS  Google Scholar 

  19. Bethell, R. et al. Evaluation of in vitro interactions between apricitabine and other deoxycytidine analogues. Antimicrob. Agents Chemother. 21 May 2007 (doi:10.1128/AAC.01204–06).

  20. Holdich, T., Shiveley, L. A. & Sawyer, J. Effect of lamivudine on the plasma and intracellular pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers. Antimicrob. Agents Chemother. 51, 2943–2947 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Thompson, M. A. et al. Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients. AIDS 19, 1607–1615 (2005).

    CAS  PubMed  Google Scholar 

  22. Gripshover, B. M. et al. Amdoxovir versus placebo with enfuvirtide plus optimized background therapy for HIV-1-infected subjects failing current therapy (AACTG A5118). Antiviral Ther. 11, 619–623 (2006).

    CAS  Google Scholar 

  23. Narayanasamy, J. et al. Synthesis and anti-HIV activity of (-)-β-D-(2R, 4R)-1, 3-dioxolane-2, 6-diamino purine (DAPD) (amdoxovir) and (-)-β-D-(2R, 4R)-1, 3-dioxolane guanosine (DXG) prodrugs. Antiviral Res. 75, 198–209 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ghosn, J. et al. Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial. HIV Med. 8, 142–147 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  26. Hang, J. Q. et al. Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biochem. Biophys. Res. Commun. 352, 341–350 (2007).

    CAS  PubMed  Google Scholar 

  27. Goebel, F. et al. Short-term antiviral activity of TMC278: a novel NNRTI in treatment-naive HIV-1-infected subjects. AIDS 20, 1721–1726 (2006).

    CAS  PubMed  Google Scholar 

  28. The TMC125-C223 Writing Group. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 21, F1–F10 (2007).

  29. Boffito, M. et al. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. AIDS 21, 1449–1455 (2007).

    CAS  PubMed  Google Scholar 

  30. Vingerhoets, J. et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J. Virol. 79, 12773–12782 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jespers, V. A. et al. Dose-ranging phase 1 study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers. J. Acquir. Immune Defic. Syndr. 44, 154–158 (2007).

    CAS  PubMed  Google Scholar 

  32. Malcolm, R. K., Woolfson, A. D., Toner, C. F., Morrow, R. J. & McCullagh, S. D. Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. J. Antimicrob. Chemother. 56, 954–956 (2005).

    CAS  PubMed  Google Scholar 

  33. Woolfson, A. D., Malcolm, R. K., Morrow, R. J., Toner, C. F. & McCullagh, S. D. Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide. Int. J. Pharm. 325, 82–89 (2006).

    CAS  PubMed  Google Scholar 

  34. De Francesco, R. & Migliaccio, G. Challenges and successes in developing new therapies for hepatitis C. Nature 436, 953–960 (2005).

    CAS  PubMed  Google Scholar 

  35. Carroll, S. S. et al. Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. 278, 11979–11984 (2003).

    CAS  PubMed  Google Scholar 

  36. Tomassini, J. E. et al. Inhibitory effect of 2′-substituted nucleosides on hepatitis C virus replication correlates with metabolic properties in replicon cells. Antimicrob. Agents Chemother. 49, 2050–2058 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Migliaccio, G. et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem. 278, 49164–49170 (2003).

    CAS  PubMed  Google Scholar 

  38. Eldrup, A. B. et al. Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 47, 2283–2295 (2004).

    CAS  PubMed  Google Scholar 

  39. Olsen, D. B. et al. A 7-deaza-adeosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48, 3944–3953 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Carroll, S. et al. Nucleoside inhibitors of hepatitis C virus RNA polymerase: improved potency and liver targeting with 7-deaza-7-fluoro-2′-C-methyladenosine. Late Breakers, Twentieth International Conference on Antiviral Research, Palm Springs, California, USA 2007, LB-01.

  41. Stuyver, L. J. et al. Inhibition of hepatitis C replicon RNA synthesis by β-D-2′-deoxy-2′-fluoro-2′-C-methylcytidine: a specific inhibitor of hepatitis C virus replication. Antiviral Chem. Chemother. 17, 79–87 (2006).

    CAS  Google Scholar 

  42. Klumpp, K. et al. The novel nucleoside analog R1479 (4′-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture. J. Biol. Chem. 281, 3793–3799 (2006). Among the nucleoside RNA replicase inhibitors (NRRIs), one of the more promising drug candidates for the treatment of HCV infections.

    CAS  PubMed  Google Scholar 

  43. Klumpp, K. et al. Design and characterization of R1626, a prodrug of the HCV replication inhibitor R1479 (4′-azidocytidine) with enhanced oral bioavailability. Antiviral Res. 74, A35, abstract 21 (2007).

    Google Scholar 

  44. Smith, D. et al. Novel 4′-azido-2′-deoxy-nucleoside analogs are potent inhibitors of NS5B-dependent HCV replication. Antiviral Res. 74, A36, abstract 22 (2007).

    Google Scholar 

  45. Afdhal, N. et al. Final phase I/II trial results for NM283, a new polymerase inhibitor for hepatitis C: antiviral efficacy and tolerance in patients with HCV-1 infection, including previous interferon failures. Hepatology 726A (2004).

  46. Coelmont, L. et al. Ribavirin antagonizes the in vitro anti-hepatitis C virus activity of 2′-C-methylcytidine, the active component of valopicitabine. Antimicrob. Agents Chemother. 50, 3444–3446 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Le Pogam, S. et al. In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology 351, 349–359 (2006).

    CAS  PubMed  Google Scholar 

  48. Summa, V. et al. Discovery of α, γ-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. J. Med. Chem. 47, 14–17 (2004).

    CAS  PubMed  Google Scholar 

  49. Summa, V. et al. HCV NS5b RNA-dependent RNA polymerase inhibitors: from α, γ-diketoacids to 4, 5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis. J. Med. Chem. 47, 5336–5339 (2004).

    CAS  PubMed  Google Scholar 

  50. Beaulieu, P. L. et al. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency. Bioorg. Med. Chem. Lett. 14, 967–971 (2004).

    CAS  PubMed  Google Scholar 

  51. Di Marco, S. et al. Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J. Biol. Chem. 280, 29765–29770 (2005).

    CAS  PubMed  Google Scholar 

  52. Harper, S. et al. Development and preliminary optimization of indole-N-actamide inhibitors of hepatitis C virus NS5B polymerase. J. Med. Chem. 48, 1314–1317 (2005).

    CAS  PubMed  Google Scholar 

  53. Dhanak, D. et al. Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J. Biol. Chem. 277, 38322–38327 (2002).

    CAS  PubMed  Google Scholar 

  54. Tomei, L. et al. Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides. J. Virol. 78, 938–846 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, M. et al. Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition. J. Biol. Chem. 278, 9489–9495 (2003).

    CAS  PubMed  Google Scholar 

  56. Chan, L. et al. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 1: Sulfonamides. Bioorg. Med. Chem. Lett. 14, 793–796 (2004).

    CAS  PubMed  Google Scholar 

  57. Biswal, B. K. et al. Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors. J. Biol. Chem. 280, 18202–18210 (2005).

    CAS  PubMed  Google Scholar 

  58. Howe, A. Y. et al. Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother. 48, 4813–4821 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou, Y. et al. Potent HCV NS5B polymerase inhibitors derived from 5-hydroxy-3(2H)-pyridazinones: Part I. Exploration of pyridazinone 4-substituent variation. Antiviral Res. 74, A38, abstract 27 (2007).

    Google Scholar 

  60. Zhou, Y. et al. Potent HCV NS5B polymerase inhibitors derived from 5-hydroxy-3(2H)-pyridazinones: Part 2. Variation of the 2- and 6-pyridazinone substituents. Antiviral Res. 74, A51–A52, abstract 59 (2007).

    Google Scholar 

  61. Gopalsamy, A. et al. Design and synthesis of 3, 4-dihydro-1H-[1]-benzothieno[2, 3-c]pyran and 3, 4-dihydro-1H-pyrano[3, 4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase. Bioorg. Med. Chem. Lett. 16, 457–460 (2006).

    CAS  PubMed  Google Scholar 

  62. Love, R. A. et al. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. J. Virol. 77, 7575–7581 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tomei, L., Altamura, S., Paonessa, G., De Francesco, R., Migliaccio, G. HCV antiviral resistance: the impact of in vitro studies on the development of antiviral agents targeting the viral NS5B polymerase. Antiviral Chem. Chemother. 16, 225–245 (2005).

    CAS  Google Scholar 

  64. Baginski, S. G. et al. Mechanism of action of a pestivirus antiviral compound. Proc. Natl Acad. Sci. USA 97, 7981–7986 (2000).

    CAS  PubMed  Google Scholar 

  65. Paeshuyse, J. et al. A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase. J. Virol. 80, 149–160 (2006). Description of a new class of non-nucleoside RNA replicase inhibitors (NNRRIs) that showed potent activity against pestiviruses and also served as starting point for development of new anti-HCV compounds (now in clinical development).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pürstinger, G., Paeshuyse, J., De Clercq, E. & Neyts, J. Antiviral 2, 5-disubstituted imidazo-[4, 5-c]pyridines: from anti-pestivirus to anti-hepatitis C virus activity. Bioorg. Med. Chem. Lett. 17, 390–393 (2007).

    Google Scholar 

  67. Vliegen, I. et al. Substituted imidazopyridines as potent inhibitors of hepatitis C virus replication that target the viral polymerase. Antiviral Res. 74, A37, abstract 26 (2007).

    Google Scholar 

  68. Cahn, P. et al. Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIV-infected patients: 24-week results of the RESIST-2 trial. Clin. Infect. Dis. 43, 1347–1356 (2006).

    CAS  PubMed  Google Scholar 

  69. Gathe, J. et al. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin. Infect. Dis. 43, 1337–1346 (2006).

    CAS  PubMed  Google Scholar 

  70. Lalezari, J. P., Ward, D. J., Tomkins, S. A. & Garges, H. P. Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006. J. Antimicrob. Chemother. 60, 170–174 (2007).

    CAS  PubMed  Google Scholar 

  71. Ford, S. L. et al. Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor. Antimicrob. Agents Chemother. 50, 2201–2206 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Reddy, Y. S. et al. Safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus type 1 protease inhibitor, following repeat administration with and without ritonavir in healthy adult subjects. Antimicrob. Agents Chemother. 51, 1202–1208 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Brecanavir's hopes dashed. AIDS Patients Care STDs 21, 143 (2007).

  74. Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189 (2003). Ciluprevir (BILN 2061), although no longer pursued, was the first protease inhibitor described for HCV shown to have antiviral activity in humans.

    CAS  PubMed  Google Scholar 

  75. Lin, C. et al. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 279, 17508–17514 (2004).

    CAS  PubMed  Google Scholar 

  76. Venkatraman, S. et al. Discovery of (1R, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2, 3-dioxopropyl]- 3-[2(S)-[[[(1, 1-dimethylethyl)amino]carbonyl]-amino]-3, 3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-aza-bicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection. J. Med. Chem. 49, 6074–6086 (2006).

    CAS  PubMed  Google Scholar 

  77. Malcolm, B. A. et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob. Agents Chemother. 50, 1013–1020 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Prongay, A. J. et al. Discovery of the HCV NS3/4A protease inhibitor (1R, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2, 3-dioxopropyl]-3-[2(S)-[[[(1, 1-dimethylethyl)amino]carbonyl]-amino]-3, 3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization. J. Med. Chem. 50, 2310–2318 (2007).

    CAS  PubMed  Google Scholar 

  79. Yi, M. et al. Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. J. Biol. Chem. 281, 8205–8215 (2006).

    CAS  PubMed  Google Scholar 

  80. Bogen, S. L. et al. Discovery of SCH446211 (SCH6): a new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication. J. Med. Chem. 49, 2750–2757 (2006).

    CAS  PubMed  Google Scholar 

  81. Hinrichsen, H. et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127, 1347–1355 (2004).

    CAS  PubMed  Google Scholar 

  82. Thibeault, D. et al. Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061. J. Virol. 78, 7352–7359 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Tong, X. et al. Impact of naturally occurring variants of HCV protease on the binding of different classes of protease inhibitors. Biochemistry 45, 1353–1361 (2006).

    CAS  PubMed  Google Scholar 

  84. Perni, R. B. et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3–4A serine protease. Antimicrob. Agents Chemother. 50, 899–909 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lin, K., Perni, R. B., Kwong, A. D. & Lin, C. VX-950, a novel hepatitis C virus (HCV) NS3–4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells. Antimicrob. Agents Chemother. 50, 1813–1822 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Sarrazin, C. et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132, 1767–1777 (2007).

    CAS  PubMed  Google Scholar 

  87. Lin, C. et al. In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 280, 36784–36791 (2005).

    CAS  PubMed  Google Scholar 

  88. Zhou, Y. et al. Phenotypic and structural analyses of HCV NS3 protease ARG155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J. Biol. Chem. 6 June 2007 (doi:10.1074/jbc.M610207200).

    CAS  PubMed  Google Scholar 

  89. Courcambeck, J. et al. Resistance of hepatitis C virus to NS3–4A protease inhibitors: mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations. Antiviral Ther. 11, 847–855 (2006).

    CAS  Google Scholar 

  90. Matthews, T. et al. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nature Rev. Drug Discov. 3, 215–225 (2004). Enfuvirtide, a 36-amino acid peptide that is homologous to part of the heptad repeat 2 (HR2) region of the viral glycoprotein gp41, is as of today the only anti-HIV drug that blocks the HIV fusion with the cell. It has to be injected subcutaneously.

    CAS  Google Scholar 

  91. Westby, M. & van der Ryst, E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antiviral Chem. Chemother. 16, 339–354 (2005).

    CAS  Google Scholar 

  92. Moradpour, D., Penin, F. & Rice, C. M. Replication of hepatitis C virus. Nature Rev. Microbiol. 5, 453–463, 2007

    CAS  Google Scholar 

  93. Myers, S. A. et al. A prospective clinical and pathological examination of injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. Antiviral Ther. 11, 935–939 (2006).

    CAS  Google Scholar 

  94. Moltó, J. et al. Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Antiviral Ther. 11, 47–51 (2006).

    Google Scholar 

  95. Raffi, F. et al. Week-12 response to therapy as a predictor of week 24, 48, and 96 outcome in patients receiving the HIV fusion inhibitor enfuvirtide in the T-20 versus Optimized Regimen Only (TORO) trials. Clin. Infect. Dis. 42, 870–877 (2006).

    PubMed  Google Scholar 

  96. Lu, J. et al. Rapid emergence of enfuvirtide resistance in HIV-1-infected patients. J. Acquir. Immune Defic. Syndr. 43, 60–64 (2006).

    CAS  PubMed  Google Scholar 

  97. Labrosse, B. et al. Role of the envelope genetic context in the development of enfuvirtide resistance in human immunodeficiency virus type 1-infected patients. J. Virol. 80, 8807–8819 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ray, N. et al. Clinical resistance to enfuvirtide does not affect susceptibility of human immunodeficiency virus type 1 to other classes of entry inhibitors. J. Virol. 81, 3240–3250 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Heredia, A. et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc. Natl Acad. Sci. USA 100, 10411–10416 (2003).

    CAS  PubMed  Google Scholar 

  100. Heredia, A. et al. Rapamycin reduces CCR5 density levels on CD4 T cells and this effect results in potentiation of Enfuvirtide (T-20) against R5 strains of HIV-1 in vitro. Antimicrob. Agents Chemother. 51, 2489–2496 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. De Clercq, E. The bicyclam AMD3100 story. Nature Rev. Drug Discovery 2, 581–587 (2003).

    CAS  Google Scholar 

  102. Dorr, P. et al. Maraviroc (UK-427857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother. 49, 4721–4732 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Fätkenheuer, G. et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nature Med. 11, 1170–1172 (2005).

    PubMed  Google Scholar 

  104. Westby, M. et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J. Virol. 80, 4909–4920 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Westby, M. et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J. Virol. 81, 2359–2371 (2007).

    CAS  PubMed  Google Scholar 

  106. Strizki, J. M. et al. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 49, 4911–4919 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Schürmann, D. et al. Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS 21, 1293–1299 (2007).

    PubMed  Google Scholar 

  108. Gulick, R. M. et al. Phase 2 Study of the safety and efficacy of Vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS Clinical Trials Group 5211. J. Infect. Dis. 196, 304–312 (2007).

    CAS  PubMed  Google Scholar 

  109. Pugach, P. et al. HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for entry. Virology 361, 212–228 (2007).

    CAS  PubMed  Google Scholar 

  110. Wilkin, T. J. et al. HIV type 1 chemokine co-receptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin. Infect. Dis. 44, 591–595 (2007).

    CAS  PubMed  Google Scholar 

  111. Murga, J. D., Franti, M., Pevear, D. C., Maddon, P. J. & Olson, W. C. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 50, 3289–3296 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ji, C. et al. CCR5 Small-molecule antagonists and monoclonal antibodies exert potent synergistic antiviral effects by cobinding to the receptor. Mol. Pharmacol. 72, 18–28 (2007).

    CAS  PubMed  Google Scholar 

  113. Sato, M. et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J. Med. Chem. 49, 1506–1508 (2006).

    CAS  PubMed  Google Scholar 

  114. Daelemans, D., Lu, R., De Clercq, E. & Engelman, A. Characterization of a replication-competent, integrase-defective human immunodeficiency virus (HIV)/simian virus 40 chimera as a powerful tool for the discovery and validation of HIV integrase inhibitors. J. Virol. 81, 4381–4385 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Markowitz, M. et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 43, 509–515 (2006).

    CAS  PubMed  Google Scholar 

  116. Markowitz, M. et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naïve HIV-1-infected patients. XVI International AIDS Conference, Toronto, Canada 2006. Abstract THLB0214.

  117. Grinsztejn, B. et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369, 1261–1269 (2007).

    CAS  PubMed  Google Scholar 

  118. DeJesus, E. et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 43, 1–5 (2006).

    CAS  PubMed  Google Scholar 

  119. Ramanathan, S., Shen, G., Cheng, A. & Kearney, B. P. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J. Acquir. Immune Defic. Syndr. 45, 274–279 (2007).

    CAS  PubMed  Google Scholar 

  120. Zolopa, A. R. et al. The HIV integrase inhibitor GS-9137 has potent antiretroviral activity in treatment-experienced patients. Oral presentations from the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, USA, 2007, 143 LB.

  121. Li, F. 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 100, 13555–13560 (2003).

    CAS  PubMed  Google Scholar 

  122. Adamson, C. S. et al. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J. Virol. 80, 10957–10971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Martin, D. E., Blum, R., Doto, J., Galbraith, H. & Ballow, C. Multiple-Dose Pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin. Pharmacokinet. 46, 589–598 (2007).

    CAS  PubMed  Google Scholar 

  124. Martin, D. E. et al. Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers. Antimicrob. Agents Chemother. 51, 3063–3066 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Wen, Z., Martin, D. E., Bullock, P., Lee, K.-H. & Smith, P. C. Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Drug Metab. Dispos. 35, 440–448 (2007).

    CAS  PubMed  Google Scholar 

  126. Rosenwirth, B. et al., Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog. Antimicrob. Agents Chemother. 38, 1763–1772 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Luban, J., Bossolt, K. L., Franke, E. K., Kalpana, G. V. & Goff, S. P. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73, 1067–1078 (1993).

    CAS  PubMed  Google Scholar 

  128. Watashi, K. et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol. Cell 19, 111–122 (2005). Recognition of cyclophilin B as a potential target for therapeutic intervention with HCV infections.

    CAS  PubMed  Google Scholar 

  129. Tan, S. L., Pause, A., Shi, Y. & Sonenberg, N. Hepatitis C therapeutics: current status and emerging strategies. Nature Rev. Drug Discov. 1, 867–881 (2002).

    CAS  Google Scholar 

  130. Rice, C. M. & You, S. Treating hepatitis C: can you teach old dogs new tricks? Hepatology 42, 1455–1458 (2005).

    PubMed  Google Scholar 

  131. Paeshuyse, J. et al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 43, 761–770 (2006). Identification of a cyclosporin derivative, now in clinical development, as a potent and selective inhibitor of HCV replication.

    CAS  PubMed  Google Scholar 

  132. Coelmont, L. et al. The cyclophilin inhibitor Debio-025 is a potent inhibitor of hepatitis C virus replication in vitro with a unique resistance profile. Antiviral Res. 74, A39, abstract 29 (2007).

    Google Scholar 

  133. McHutchison, J. G. et al. A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients. J. Hepatol. 44, 88–96 (2006).

    CAS  PubMed  Google Scholar 

  134. Krönke, J. et al. Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs. J. Virol. 78, 3436–3446 (2004).

    PubMed  PubMed Central  Google Scholar 

  135. Johnston, B. et al. shRNAs targeting hepatitis C: effects of sequence and structural features, and comparison with siRNA. Antiviral Res. 74, A59, abstract 79 (2007).

    Google Scholar 

  136. Pavlovic, D. et al. The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc. Natl Acad. Sci. USA 100, 6104–6108 (2003).

    CAS  PubMed  Google Scholar 

  137. Chapel, C. et al. Antiviral effect of α-glucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles. J. Gen. Virol. 87, 861–871 (2006).

    CAS  PubMed  Google Scholar 

  138. Hwang, D.-R. et al. Inhibition of hepatitis C virus replication by arsenic trioxide. Antimicrob. Agents Chemother. 48, 2876–2882 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hatano, H. & Deeks, S. G. Drug resistant HIV. Promising research on three new drugs gives hope for chronically infected patients. Br. Med. J. 334, 1124–1125 (2007).

    Google Scholar 

  140. Stephenson, J. Researchers buoyed by novel HIV drugs will expand drug arsenal against resistant virus. JAMA 297, 1535–1536 (2007).

    CAS  PubMed  Google Scholar 

  141. Josephson, F. et al. Antiretroviral treatment of HIV infection: Swedish recommendations 2007. Scand. J. Infect. Dis. 39, 486–507 (2007).

    CAS  PubMed  Google Scholar 

  142. Ren, J. et al. Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases. J. Med. Chem. 50, 2301–2309 (2007).

    CAS  PubMed  Google Scholar 

  143. Herschhorn, A. et al. De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants. J. Med. Chem. 50, 2370–2384 (2007).

    CAS  PubMed  Google Scholar 

  144. González de Requena, D. et al. Unexpected drug-drug interaction between tipranavir/ritonavir and enfuvirtide. AIDS 20, 1977–1979 (2006).

    PubMed  Google Scholar 

  145. The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N. Engl. J. Med. 356, 1723–1735 (2007).

  146. MacArthur, R. D. et al. A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet 368, 2125–2135.

  147. Tomei, L. et al. Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J. Virol. 77, 13225–13231 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Le Pogam, S. et al. Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus. J. Virol. 80, 6146–6154 (2006). Pointing to the specificity in their mode of action, non-nucleoside RNA replicase inhibitors (NNRRIs), akin to their NNRTI counterparts for the HIV reverse transcriptase, lead to the emergence of resistance mutations in the HCV RNA replicase.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Mo, H. et al. Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro. Antimicrob. Agents Chemother. 49, 4305–4314 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Pauwels, R. Aspects of successful drug discovery and development. Antiviral Res. 71, 77–89 (2006). Description of the paths to the successful discovery of antiretroviral agents effective against HIV infections (AIDS).

    CAS  PubMed  Google Scholar 

  151. Chen, J. C.-H. et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc. Natl Acad. Sci. USA 97, 8233–8238 (2000).

    CAS  PubMed  Google Scholar 

  152. Jones, G. et al. In vitro resistance profile of HIV-1 mutants selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, California, USA, poster 627.

  153. De Clercq, E. From adefovir to AtriplaTM via tenofovir, VireadTM and TruvadaTM. Future Virol. 1, 709–715 (2006).

    CAS  Google Scholar 

  154. Gallant, J. E. et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N. Engl. J. Med. 354, 251–260 (2006).

    CAS  PubMed  Google Scholar 

  155. Pozniak, A. L. et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naïve patients. J. Aquir. Immune Defic. Syndr. 43, 535–540 (2006). Together with reference 154, describes the efficacy and safety of the triple drug combination of tenofovir disoproxil fumarate (TDF) with emtricitabine and efavirenz in the treatment of HIV infections (AIDS).

    CAS  Google Scholar 

  156. Hoofnagle, J. H. & Seeff, L. B. Peginterferon and ribavirin for chronic hepatitis C. N. Engl. J. Med. 355, 2444–2451 (2006).

    CAS  PubMed  Google Scholar 

  157. Potter, C. W., Phair, J. P., Vodinelich, L., Fenton, R. & Jennings, R. Antiviral, immunosuppressive and antitumour effects of ribavirin. Nature 259, 496–497 (1976).

    CAS  PubMed  Google Scholar 

  158. Streeter, D. G. et al. Mechanism of action of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc. Natl Acad. Sci. USA 70, 1174–1178 (1973).

    CAS  PubMed  Google Scholar 

  159. Leyssen, P., De Clercq, E. & Neyts, J. The anti-yellow fever virus activity of ribavirin is independent of error-prone replication. Mol. Pharmacol. 69, 1461–1467 (2006).

    CAS  PubMed  Google Scholar 

  160. De Clercq, E. Antiviral agents active against influenza A viruses. Nature Rev. Drug Discov. 5, 1015–1025 (2006).

    CAS  Google Scholar 

  161. De Clercq, E. AIDS in the third world: how to stop the HIV infection? Verh. K. Acad. Geneesk. Belg. 64, 65–80 (2007).

    Google Scholar 

Download references

Acknowledgements

I would like to thank C. Callebaut for her invaluable editorial assistance.

Author information

Authors and Affiliations

  1. Rega Institute for Medical Research, K. U. Leuven, Leuven, B-3000, Belgium

    Erik De Clercq

Authors
  1. Erik De Clercq
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erik De Clercq.

Ethics declarations

Competing interests

Erik de Clercq is the co-inventor of tenofovir (disoproxil fumarate).

Supplementary information

Supplementary information S1 (figure)

Combination therapy for HIV infections. (PDF 688 kb)

Supplementary information S2 (figure)

Etravirine positioned in the NNRTI-binding site of HIV-1 reverse transcriptase. (PDF 125 kb)

Supplementary information S3 (figure)

Bovineviral diarrhoea virus (BVDV) inhibitors. (PDF 172 kb)

Supplementary information S4 (figure)

Structures of cyclosporin and its derivative Debio-025 (PDF 241 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clercq, E. The design of drugs for HIV and HCV. Nat Rev Drug Discov 6, 1001–1018 (2007). https://doi.org/10.1038/nrd2424

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2424

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing