1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pharmacology and Toxicology
  4. Volume 51, 2011
  5. Article

Annual Review of Pharmacology and Toxicology

Volume 51, 2011

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

Abstract

My search for a selective antiviral chemotherapy started more than 40 years ago with interferon inducers, then shifted to nucleoside analogs with the discovery of BVDU (brivudin), a highly selective anti-HSV-1 and anti-VZV agent, and to dideoxynucleoside analogs such as d4T (stavudine), anti-HIV agents. The search culminated in the discovery of acyclic nucleoside phosphonates (ANPs) (in collaboration with Antonin Holý), a key class of compounds active against HIV, hepatitis B virus, and DNA viruses at large; the best known of these compounds is tenofovir. Along the way, the principle of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was established. This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an “ideal” NNRTI.

Keyword(s): acyclovir, ANPs, Autobiography, BVDU, HAART, interferon, NNRTIs, NRTIs, NtRTIs, poly(I).poly(C)
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010510-100228
2011-02-10
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/51/1/annurev-pharmtox-010510-100228.html?itemId=/content/journals/10.1146/annurev-pharmtox-010510-100228&mimeType=html&fmt=ahah

Literature Cited

  1. De Clercq E, Merigan TC. 1.  1970. Current concepts of interferon and interferon induction. Annu. Rev. Med. 21:17–46 [Google Scholar]
  2. De Somer P, De Clercq E, Billiau A, Schonne E. 2.  1967. Urinary excretion of interferon in rabbits. Proc. First Int. Conf. Vaccines against Viral Ricketts. Diseas. Man650–52 Washington, DC: Pan Am. Health Organ. [Google Scholar]
  3. De Somer P, De Clercq E, Billiau A, Schonne E, Claesen M. 3.  1968. Antiviral activity of polyacrylic and polymethacrylic acids. I. Mode of action in vitro. J. Virol. 2:878–85 [Google Scholar]
  4. De Somer P, De Clercq E, Billiau A, Schonne E, Claesen M. 4.  1968. Antiviral activity of polyacrylic and polymethacrylic acids. II. Mode of action in vivo. J. Virol. 2:886–93 [Google Scholar]
  5. De Clercq E, Merigan TC. 5.  1969. Requirement of a stable secondary structure for the antiviral activity of polynucleotides. Nature 222:1148–52 [Google Scholar]
  6. De Clercq E, Wells RD, Merigan TC. 6.  1970. Increase in antiviral activity of polynucleotides by thermal activation. Nature 226:364–66 [Google Scholar]
  7. De Clercq E, Eckstein F, Merigan TC. 7.  1969. Interferon induction increased through chemical modification of a synthetic polyribonucleotide. Science 165:1137–39 [Google Scholar]
  8. De Clercq E, Nuwer MR, Merigan TC. 8.  1970. The role of interferon in the protective effect of a synthetic double-stranded polyribonucleotide against intranasal vesicular stomatitis virus challenge in mice. J. Clin. Investig. 49:1565–77 [Google Scholar]
  9. De Clercq E, Wells RD, Grant RC, Merigan TC. 9.  1971. Thermal activation of the antiviral activity of synthetic double-stranded polyribonucleotides. J. Mol. Biol. 56:83–100 [Google Scholar]
  10. De Clercq E, De Somer P. 10.  1971. Antiviral activity of polyribocytidylic acid in cells primed with polyriboinosinic acid. Science 173:260–62 [Google Scholar]
  11. Merigan TC. 11.  1967. Induction of circulating interferon by synthetic anionic polymers of known composition. Nature 214:416–17 [Google Scholar]
  12. Merigan TC, Regelson W. 12.  1967. Interferon induction in man by a synthetic polyanion of defined composition. N. Engl. J. Med. 277:1283–87 [Google Scholar]
  13. Isaacs A, Lindenmann J. 13.  1957. Virus interference. I. Interferon. Proc. R. Soc. Lond. Ser. B 147:258–67 [Google Scholar]
  14. Lampson GP, Tytell AA, Field AK, Nemes MM, Hilleman MR. 14.  1967. Inducers of interferon and host resistance. I. Double-stranded RNA from extracts of Penicillium funiculosum. Proc. Natl. Acad. Sci. USA 58:782–89 [Google Scholar]
  15. Field AK, Tytell AA, Lampson GP, Hilleman MR. 15.  1967. Inducers of interferon and host resistance. II. Multistranded synthetic polynucleotide complexes. Proc. Natl. Acad. Sci. USA 58:1004–10 [Google Scholar]
  16. Tytell AA, Lampson GP, Field AK, Hilleman MR. 16.  1967. Inducers of interferon and host resistance. III. Double-stranded RNA from reovirus type 3 virions (reo 3-RNA). Proc. Natl. Acad. Sci. USA 58:1719–22 [Google Scholar]
  17. Field AK, Lampson GP, Tytell AA, Nemes MM, Hilleman MR. 17.  1967. Inducers of interferon and host resistance. IV. Double-stranded replicative form RNA (MS2-Ff-RNA) from E. coli infected with MS2 coliphage. Proc. Natl. Acad. Sci. USA 58:2102–8 [Google Scholar]
  18. Field AK, Tytell AA, Lampson GP, Hilleman MR. 18.  1968. Inducers of interferon and host resistance. V. In vitro studies. Proc. Natl. Acad. Sci. USA 61:340–46 [Google Scholar]
  19. Offit PA. 19.  2007. Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases New York: HarperCollins254
  20. Carter WA, De Clercq E. 20.  1974. Viral infection and host defense. Science 186:1172–78 [Google Scholar]
  21. Derynck R, Content J, De Clercq E, Volckaert G, Tavernier J. 21.  et al. 1980. Isolation and structure of a human fibroblast interferon gene. Nature 285:542–47 [Google Scholar]
  22. Derynck R, Remaut E, Saman E, Stanssens P, De Clercq E. 22.  et al. 1980. Expression of the human fibroblast interferon gene in Escherichia coli. Nature 287:193–97 [Google Scholar]
  23. Content J, De Wit L, Pierard D, Derynck R, De C. 23.  1982. Secretory proteins induced in human fibroblasts under conditions used for the production of interferon β. . Proc. Natl. Acad. Sci. USA 79:2768–72 [Google Scholar]
  24. De Clercq E. 24.  1982. Interferon: a molecule for all seasons. Virus Infections: Modern Concepts and Status LC Olsen 87–138 New York: Marcel Dekker [Google Scholar]
  25. De Clercq E. 25.  2006. Interferon and its inducers—a never-ending story: “old” and “new” data in a new perspective. J. Infect. Dis. 194:Suppl. 1S19–26 [Google Scholar]
  26. De Clercq E. 26.  2002. Antiviral activity of nucleoside analogues: the BVDU connection. Recent Advances in Nucleosides: Chemistry and Chemotherapy CK Chu 433–54 New York: Elsevier [Google Scholar]
  27. De Clercq E. 27.  2004. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem. Pharmacol. 68:2301–15 [Google Scholar]
  28. De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS. 28.  et al. 1979. (E)-5-(2-bromovinyl)-2′-deoxyuridine: a potent and selective anti-herpes agent. Proc. Natl. Acad. Sci. USA 76:2947–51 [Google Scholar]
  29. De Clercq E, Degreef H, Wildiers J, de Jonge G, Drochmans A. 29.  et al. 1980. Oral (E)-5-(2-bromovinyl)-2′-deoxyuridine in severe herpes zoster. Br. Med. J. 281:1178 [Google Scholar]
  30. De Clercq E. 30.  2009. Looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective. Adv. Virus Res. 73:1–53 [Google Scholar]
  31. Maudgal PC, De Clercq E, Descamps J, Missotten L, De Somer P. 31.  et al. 1980. (E)-5-(2-bromovinyl)-2′-deoxyuridine in the treatment of experimental herpes simplex keratitis. Antimicrob. Agents Chemother. 17:8–12 [Google Scholar]
  32. Maudgal PC, Missotten L, De Clercq E, Descamps J, De Meuter E. 32.  1981. Efficacy of (E)-5-(2-bromovinyl)-2′-deoxyuridine in the topical treatment of herpes simplex keratitis. Albrecht von Graefes Arch. Klin. Ophthalmol. 216:261–68 [Google Scholar]
  33. Maudgal PC, De Clercq E, Missotten L. 33.  1984. Efficacy of bromovinyldeoxyuridine in the treatment of herpes simplex virus and varicella-zoster virus eye infections. Antiviral Res. 4:281–91 [Google Scholar]
  34. Maudgal PC, De Clercq E, Descamps J, Missotten L, Wijnhoven J. 34.  1982. Experimental stromal herpes simplex keratitis: influence of treatment with topical bromovinyldeoxyuridine and trifluridine. Arch. Ophthalmol. 100:653–56 [Google Scholar]
  35. Maudgal PC, Uyttebroeck W, De Clercq E, Missotten L. 35.  1982. Oral and topical treatment of experimental herpes simplex iritis with bromovinyldeoxyuridine. Arch. Ophthalmol. 100:1337–40 [Google Scholar]
  36. Maudgal PC, De Clercq E. 36.  1991. Bromovinyldeoxyuridine treatment of herpetic keratitis clinically resistant to other antiviral agents. Curr. Eye Res. 10:Suppl.193–99 [Google Scholar]
  37. De Clercq E. 37.  2003. Highly potent and selective inhibition of varicella-zoster virus replication by bicyclic furo[2,3-d]pyrimidine nucleoside analogues. Med. Res. Rev. 23:253–74 [Google Scholar]
  38. McGuigan C, Yarnold CJ, Jones G, Velázquez S, Barucki H. 38.  et al. 1999. Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base. J. Med. Chem. 42:4479–84 [Google Scholar]
  39. McGuigan C, Barucki H, Blewett S, Carangio A, Erichsen JT. 39.  et al. 2000. Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain. J. Med. Chem. 43:4993–97 [Google Scholar]
  40. Andrei G, Sienaert R, McGuigan C, De Clercq E, Balzarini J. 40.  et al. 2005. Susceptibilities of several clinical varicella-zoster virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides. Antimicrob. Agents Chemother. 49:1081–86 [Google Scholar]
  41. De Clercq E. 41.  2009. Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med. Res. Rev. 29:571–610 [Google Scholar]
  42. McGuigan C, Pathirana RN, Migliore M, Adak R, Luoni G. 42.  et al. 2007. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus. J. Antimicrob. Chemother. 60:1316–30 [Google Scholar]
  43. Schaeffer HJ, Beauchamp L, de Miranda P, Elion GB, Bauer DJ. 43.  et al. 1978. 9-(2-Hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature 272:583–85 [Google Scholar]
  44. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L. 44.  et al. 1977. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc. Natl. Acad. Sci. USA 74:5716–20 [Google Scholar]
  45. Colla L, De Clercq E, Busson R, Vanderhaeghe H. 45.  1983. Synthesis and antiviral activity of water-soluble esters of acyclovir [9-(2-hydroxyethoxymethyl)guanine]. J. Med. Chem. 26:602–4 [Google Scholar]
  46. Maudgal PC, De Clercq E, Descamps J, Missotten L. 46.  1984. Topical treatment of experimental herpes simplex keratouveitis with 2′-O-glycylacyclovir: a water-soluble ester of acyclovir. Arch. Ophthalmol. 102:140–42 [Google Scholar]
  47. Beauchamp LM, Orr GF, de Miranda P, Burnette T, Krenitsky TA. 47.  1992. Amino acid ester prodrugs of acyclovir. Antiviral Chem. Chemother. 3:157–64 [Google Scholar]
  48. De Clercq E, Field HJ. 48.  2006. Antiviral prodrugs—the development of successful prodrug strategies for antiviral chemotherapy. Br. J. Pharmacol. 147:1–11 [Google Scholar]
  49. Krenitsky TA, Hall WW, de Miranda P, Beauchamp LM, Schaeffer HJ. 49.  et al. 1984. 6-Deoxyacyclovir: a xanthine oxidase-activated prodrug of acyclovir. Proc. Natl. Acad. Sci. USA 81:3209–13 [Google Scholar]
  50. Rashidi MR, Smith JA, Clarke SE, Beedham C. 50.  1997. In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. Drug Metab. Dispos. 25:805–13 [Google Scholar]
  51. De Clercq E, Balzarini J, Descamps J, Eckstein F. 51.  1980. Antiviral, antimetabolic and antineoplastic activities of 2′- or 3′-amino- or -azido-substituted deoxyribonucleosides. Biochem. Pharmacol. 29:1849–51 [Google Scholar]
  52. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN. 52.  et al. 1985. 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 82:7096–100 [Google Scholar]
  53. Mitsuya H, Broder S. 53.  1986. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc. Natl. Acad. Sci. USA 83:1911–15 [Google Scholar]
  54. Furman PA, Fyfe JA, St Clair MH, Weinhold K, Rideout JL. 54.  et al. 1986. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc. Natl. Acad. Sci. USA 83:8333–37 [Google Scholar]
  55. Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J. 55.  et al. 1987. 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. 142:128–34 [Google Scholar]
  56. Lin TS, Schinazi RF, Prusoff WH. 56.  1987. Potent and selective in vitro activity of 3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus. Biochem. Pharmacol. 36:2713–18 [Google Scholar]
  57. Hamamoto Y, Nakashima H, Matsui T, Matsuda A, Ueda T. 57.  et al. 1987. Inhibitory effect of 2′,3′-didehydro-2′,3′-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immuno-deficiency virus. Antimicrob. Agents Chemother. 31:907–10 [Google Scholar]
  58. Martin JC, Hitchcock MJM, De Clercq E, Prusoff WH. 58.  2010. Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res. 85:34–38 [Google Scholar]
  59. Soudeyns H, Yao XI, Gao Q, Belleau B, Kraus JL. 59.  et al. 1991. Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2′-deoxy-3′-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. Antimicrob. Agents Chemother. 35:1386–90 [Google Scholar]
  60. Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH. 60.  et al. 1997. 1592U89, a novel carbocyclic nucleoside analog with potent, selective antihuman immunodeficiency virus activity. Antimicrob. Agents Chemother. 41:1082–93 [Google Scholar]
  61. Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM. 61.  et al. 1992. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob. Agents Chemother 36:2423–31 [Google Scholar]
  62. De Clercq E. 62.  2009. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int. J. Antimicrob. Agents 33:307–20 [Google Scholar]
  63. De Clercq E. 63.  2009. The history of antiretrovirals: key discoveries over the past 25 years. Rev. Med. Virol. 19:287–99 [Google Scholar]
  64. Cihlar T, Ray AS. 64.  2010. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 85:39–58 [Google Scholar]
  65. Herdewijn P, Balzarini J, De Clercq E, Pauwels R, Baba M. 65.  et al. 1987. 3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J. Med. Chem. 30:1270–78 [Google Scholar]
  66. De Clercq E, Holý A. 66.  2005. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat. Rev. Drug Discov. 4:928–40 [Google Scholar]
  67. De Clercq E, Descamps J, De Somer P, Holý A. 67.  1978. (S)-9-(2,3-Dihydroxypropyl)adenine: an aliphatic nucleoside analog with broad spectrum antiviral activity. Science 200:563–65 [Google Scholar]
  68. Votruba I, Holý A. 68.  1980. Inhibition of S-adenosyl-l-homocysteine hydrolase by the aliphatic nucleoside analog 9-(S)-(2,3-dihydroxypropyl)adenine. Collect. Czech. Chem. Commun. 45:3039–44 [Google Scholar]
  69. De Clercq E. 69.  1987. S-adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Biochem. Pharmacol. 36:2567–75 [Google Scholar]
  70. De Clercq E. 70.  2007. The acyclic nucleoside phosphonates from inception to clinical use: historical perspective. Antiviral Res. 75:1–13 [Google Scholar]
  71. De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J. 71.  et al. 1986. A novel selective broad-spectrum anti-DNA virus agent. Nature 323:464–67 [Google Scholar]
  72. De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J. 72.  et al. 1987. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 8:261–72 [Google Scholar]
  73. De Clercq E. 73.  2003. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin. Microbiol. Rev. 16:569–96 [Google Scholar]
  74. De Clercq E. 74.  2009. Another ten stories in antiviral drug discovery (part C): “old” and “new” antivirals, strategies and perspectives. Med. Res. Rev. 29:611–45 [Google Scholar]
  75. De Clercq E. 75.  2010. Yet another ten stories on antiviral drug discovery (part D): paradigms, paradoxes, and paraductions. Med. Res. Rev. 30:667–707 [Google Scholar]
  76. De Clercq E. 76.  2010. The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Med. Res. Rev. In press, doi:10.1002/med.20179
  77. Stittelaar KJ, Neyts J, Naesens L, van Amerongen G, van Lavieren RF. 77.  et al. 2006. Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection. Nature 439:745–48 [Google Scholar]
  78. Hostetler KY. 78.  2009. Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. Antiviral Res. 82:A84–98 [Google Scholar]
  79. Pauwels R, Balzarini J, Schols D, Baba M, Desmyter J. 79.  et al. 1988. Phosphonylmethoxyethyl purine derivatives, a new class of antihuman immunodeficiency virus agents. Antimicrob. Agents Chemother. 32:1025–30 [Google Scholar]
  80. Starrett JE Jr, Tortolani DR, Hitchcock MJ, Martin JC, Mansuri MM. 80.  1992. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. Antiviral Res. 19:267–73 [Google Scholar]
  81. Cundy KC, Sue IL, Visor GC, Marshburn J, Nakamura C. 81.  et al. 1997. Oral formulations of adefovir dipivoxil: in vitro dissolution and in vivo bioavailability in dogs. J. Pharm. Sci. 86:1334–38 [Google Scholar]
  82. Yokota T, Konno K, Chonan E, Mochizuki S, Kojima K. 82.  et al. 1990. Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro. Antimicrob. Agents Chemother. 34:1326–30 [Google Scholar]
  83. Yokota T, Mochizuki S, Konno K, Mori S, Shigeta S. 83.  et al. 1991. Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis. Antimicrob. Agents Chemother. 35:394–97 [Google Scholar]
  84. Heijtink RA, de Wilde GA, Kruining J, Berk L, Balzarini J. 84.  et al. 1993. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res. 21:141–53 [Google Scholar]
  85. Heijtink RA, Kruining J, de Wilde GA, Balzarini J, De Clercq E. 85.  et al. 1994. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob. Agents Chemother. 38:2180–82 [Google Scholar]
  86. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G. 86.  et al. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 348:800–7 [Google Scholar]
  87. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W. 87.  et al. 2003. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 348:808–16 [Google Scholar]
  88. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA. 88.  et al. 2008. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N. Engl. J. Med. 359:2442–55 [Google Scholar]
  89. Hadziyannis SJ, Tassopoulos NC, Heahtcote EJ, Chang TT, Kitis G. 89.  et al. 2005. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 352:2673–81 [Google Scholar]
  90. Balzarini J, Holý A, Jindrich J, Dvorakova H, Hao Z. 90.  et al. 1991. 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. Proc. Natl. Acad. Sci. USA 88:4961–65 [Google Scholar]
  91. Balzarini J, Holý A, Jindrich J, Naesens L, Snoeck R. 91.  et al. 1993. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother 37:332–38 [Google Scholar]
  92. Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. 92.  1998. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)-PMPA. Antimicrob. Agents Chemother. 42:612–17 [Google Scholar]
  93. Naesens L, Bischofberger N, Augustijns P, Annaert P, Van den Mooter G. 93.  et al. 1998. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob. Agents Chemother. 42:1568–73 [Google Scholar]
  94. De Clercq E. 94.  2010. Tenofovir disoproxil fumarate (TDF): discovery and clinical development. Antiviral Drugs: Biology, Chemistry, Clinic WM Kazmierski Hoboken, NJ: Wiley In press [Google Scholar]
  95. Holý A, Votruba I, Masojídková M, Andrei G, Snoeck R. 95.  et al. 2002. 6-[2-(Phosphonomethoxy)alkoxy]pyrimidines with antiviral activity. J. Med. Chem. 45:1918–29 [Google Scholar]
  96. De Clercq E, Andrei G, Balzarini J, Leyssen P, Naesens L. 96.  et al. 2005. Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids 34:331–41 [Google Scholar]
  97. Hocková D, Holý A, Masojídková M, Andrei G, Snoeck R. 97.  et al. 2003. 5-Substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines—acyclic nucleoside phosphonate analogues with antiviral activity. J. Med. Chem. 46:5064–73 [Google Scholar]
  98. Wu T, Froeyen M, Kempeneers V, Pannecouque C, Wang J. 98.  et al. 2005. Deoxythreosyl phosphonate nucleosides as selective anti-HIV agents. J. Am. Chem. Soc. 127:5056–65 [Google Scholar]
  99. Krecmerová M, Holý A, Pískala A, Masojídková M, Andrei G. 99.  et al. 2007. Antiviral activity of triazine analogues of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (cidofovir) and related compounds. J. Med. Chem. 50:1069–77 [Google Scholar]
  100. Krečmerová M, Holý A, Pohl R, Masojídková M, Andrei G. 100.  et al. 2007. Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity. J. Med. Chem. 50:5765–72 [Google Scholar]
  101. Snoeck R, Holý A, Dewolf-Peeters C, Van Den Oord J, De Clercq E. 101.  et al. 2002. Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures. Antimicrob. Agents Chemother. 46:3356–61 [Google Scholar]
  102. Dal Pozzo F, Andrei G, Holý A, Van Den Oord J, Scagliarini A. 102.  et al. 2005. Activities of acyclic nucleoside phosphonates against Orf virus in human and ovine cell monolayers and organotypic ovine raft cultures. Antimicrob. Agents Chemother. 49:4843–52 [Google Scholar]
  103. Duraffour S, Snoeck R, Krečmerová M, van Den Oord J, De Vos R. 103.  et al. 2007. Activities of several classes of acyclic nucleoside phosphonates against camelpox virus replication in different cell culture models. Antimicrob. Agents Chemother. 51:4410–19 [Google Scholar]
  104. Balzarini J, Schols D, Van Laethem K, De Clercq E, Hocková D. 104.  et al. 2007. Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines. J. Antimicrob. Chemother. 59:80–86 [Google Scholar]
  105. Ying C, Holý A, Hocková D, Havlas Z, De Clercq E, Neyts J. 105.  2005. Novel acyclic nucleoside phosphonate analogues with potent antihepatitis B virus activities. Antimicrob. Agents Chemother. 49:1177–80 [Google Scholar]
  106. Naesens L, Andrei G, Votruba I, Krečmerová M, Holý A. 106.  et al. 2008. Intracellular metabolism of the new antiviral compound 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine. Biochem. Pharmacol. 76:997–1005 [Google Scholar]
  107. Lee WA, He GX, Eisenberg E, Cihlar T, Swaminathan S. 107.  et al. 2005. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob. Agents Chemother. 49:1898–906 [Google Scholar]
  108. Ray AS, Vela JE, Boojamra CG, Zhang L, Hui H. 108.  et al. 2008. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent antihuman immunodeficiency virus agent. Antimicrob. Agents Chemother. 52:648–54 [Google Scholar]
  109. Cihlar T, Ray AS, Boojamra CG, Zhang L, Hui H. 109.  et al. 2008. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob. Agents Chemother. 52:655–65 [Google Scholar]
  110. Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE. 110.  et al. 2009. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob. Agents Chemother. 53:150–56 [Google Scholar]
  111. Hatse S, Naesens L, De Clercq E, Balzarini J. 111.  1999. N6-Cyclopropyl-PMEDAP: a novel derivative of 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) with distinct metabolic, antiproliferative, and differentiation-inducing properties. Biochem. Pharmacol. 58:311–23 [Google Scholar]
  112. Naesens L, Hatse S, Segers C, Verbeken E, De Clercq E. 112.  et al. 1999. 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine: a novel prodrug of 9-(2-phosphonylmethoxyethyl)guanine with improved antitumor efficacy and selectivity in choriocarcinoma-bearing rats. Oncol. Res. 11:195–203 [Google Scholar]
  113. Reiser H, Wang J, Chong L, Watkins WJ, Ray AS. 113.  et al. 2008. GS-9219—a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-Hodgkin's lymphoma. Clin. Cancer Res. 14:2824–32 [Google Scholar]
  114. De Clercq E. 114.  1993. HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med. Res. Rev. 13:229–58 [Google Scholar]
  115. De Clercq E. 115.  1996. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome drug resistance development. Med. Res. Rev. 16:125–57 [Google Scholar]
  116. De Clercq E. 116.  1996. What can be expected from non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections?. Rev. Med. Virol. 6:97–117 [Google Scholar]
  117. De Clercq E. 117.  1998. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res. 38:153–79 [Google Scholar]
  118. De Clercq E. 118.  2004. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present and future. Chem. Biodivers. 1:44–64 [Google Scholar]
  119. Baba M, Tanaka H, De Clercq E, Pauwels R, Balzarini J. 119.  et al. 1989. Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. Biochem. Biophys. Res. Commun. 165:1375–81 [Google Scholar]
  120. Miyasaka T, Tanaka H, Baba M, Hayakawa H, Walker RT. 120.  et al. 1989. A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J. Med. Chem. 32:2507–9 [Google Scholar]
  121. Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ. 121.  et al. 1990. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343:470–74 [Google Scholar]
  122. Debyser Z, Pauwels R, Andries K, Desmyter J, Kukla M. 122.  et al. 1991. An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivatives. Proc. Natl. Acad. Sci. USA 88:1451–55 [Google Scholar]
  123. Baba M, De Clercq E, Tanaka H, Ubasawa M, Takashima H. 123.  et al. 1991. Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci. USA 88:2356–60 [Google Scholar]
  124. Baba M, De Clercq E, Tanaka H, Ubasawa M, Takashima H. 124.  et al. 1991. Highly potent and selective inhibition of human immunodeficiency virus type 1 by a novel series of 6-substituted acyclouridine derivatives. Mol. Pharmacol. 39:805–10 [Google Scholar]
  125. Baba M, Shigeta S, Yuasa S, Takashima H, Sekiya K. 125.  et al. 1994. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob. Agents Chemother. 38:688–92 [Google Scholar]
  126. Szczech GM, Furman P, Painter GR, Barry DW, Borroto-Esoda K. 126.  et al. 2000. Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 44:123–30 [Google Scholar]
  127. Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D. 127.  et al. 1988. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20:309–21 [Google Scholar]
  128. Pannecouque C, Daelemans D, De Clercq E. 128.  2008. Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years later. Nat. Protoc. 3:427–34 [Google Scholar]
  129. Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D. 129.  et al. 1993. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of α-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci. USA 90:1711–15 [Google Scholar]
  130. Ludovici DW, Kukla MJ, Grous PG, Krishnan S, Andries K. 130.  et al. 2001. Evolution of anti-HIV drug candidates. Part 1: From α-anilinophenylacetamide (α-APA) to imidoyl thiourea (ITU). Bioorg. Med. Chem. Lett. 11:2225–28 [Google Scholar]
  131. Ludovici DW, Kavash RW, Kukla MJ, Ho CY, Ye H. 131.  et al. 2001. Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. Bioorg. Med. Chem. Lett. 11:2229–34 [Google Scholar]
  132. Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY. 132.  et al. 2001. Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg. Med. Chem. Lett. 11:2235–39 [Google Scholar]
  133. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M. 133.  et al. 2004. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 48:4680–86 [Google Scholar]
  134. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M. 134.  et al. 2005. 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-pyrimidinyl]amino]-benzonitrile (R278474, rilpivirine). J. Med. Chem. 48:1901–9 [Google Scholar]
  135. Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G. 135.  et al. 2010. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob. Agents Chemother. 54:718–27 [Google Scholar]
  136. De Clercq E. 136.  2011. From TIBO to rilpivirine: the chronicle of the discovery of the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI). Antiviral Drug Strategies E De Clercq Weinheim, Germany: Wiley-VCH Verlag In press [Google Scholar]
  137. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV. 137.  et al. 2009. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374:796–806 [Google Scholar]
  138. De Clercq E. 138.  2009. A new drug combination therapy for treatment-naïve patients with HIV-1 infection, consisting of raltegravir, emtricitabine and tenofovir disoproxil fumarate. Expert Opin. Pharmacother. 10:2935–37 [Google Scholar]
  139. Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR. 139.  et al. 2006. The survival benefits of AIDS treatment in the United States. J. Infect. Dis. 194:11–19 [Google Scholar]
  140. Hirsch MS. 140.  2007. Entecavir surprise. N. Engl. J. Med. 356:2641–43 [Google Scholar]
  141. Willyard C. 141.  2009. A preemptive strike against HIV. Nat. Med. 15:126–29 [Google Scholar]
  142. Tsai CC, Follis KE, Sabo A, Beck TW, Grant RF. 142.  et al. 1995. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 270:1197–99 [Google Scholar]
  143. Otten RA, Smith DK, Adams DR, Pullium JK, Jackson E. 143.  et al. 2000. Efficacy of postexposure prophylaxis after intravaginal exposure of pig-tailed macaques to a human-derived retrovirus (human immunodeficiency virus type 2). J. Virol. 74:9771–75 [Google Scholar]
  144. Van Rompay KK, McChesney MB, Aguirre NL, Schmidt KA, Bischofberger N. 144.  et al. 2001. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J. Infect. Dis. 184:429–38 [Google Scholar]
  145. Karim QA, Karim SSA, Frohlich JA, Grobler AC, Baxter C. 145.  et al. 2010. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329:1168–74 [Google Scholar]
  146. De Clercq E. 146.  2006. Antiviral agents active against influenza A viruses. Nat. Rev. Drug Discov. 5:1015–25 [Google Scholar]
  147. von Itzstein M. 147.  2007. The war against influenza: discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 6:967–74 [Google Scholar]
  148. Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F. 148.  et al. 2007. The way forward in HCV treatment—finding the right path. Nat. Rev. Drug Discov. 6:991–1000 [Google Scholar]
  149. De Clercq E. 149.  2007. The design of drugs for HIV and HCV. Nat. Rev. Drug Discov. 6:1001–18 [Google Scholar]
  150. De Clercq E. 150.  2003. The bicyclam AMD3100 story. Nat. Rev. Drug Discov. 2:581–87 [Google Scholar]
  151. De Clercq E. 151.  2009. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem. Pharmacol. 77:1655–64 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010510-100228
Loading
A 40-Year Journey in Search of Selective Antiviral Chemotherapy*
Annual Review of Pharmacology and Toxicology 51, 1 (2011); https://doi.org/10.1146/annurev-pharmtox-010510-100228
/content/journals/10.1146/annurev-pharmtox-010510-100228
/content/journals/10.1146/annurev-pharmtox-010510-100228
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error