Skip to main content
PMC home page
The Yale Journal of Biology and Medicine logoLink to The Yale Journal of Biology and Medicine
. 1989 Mar-Apr;62(2):215–225.

Approaches to antiviral drug development.

W H Prusoff 1, T S Lin 1, E M August 1, T G Wood 1, M E Marongiu 1
PMCID: PMC2589208  PMID: 2773516

Abstract

At present, only a few drugs have been approved by the FDA for therapy of viral infections in humans. There is a great need for antiviral drugs with increased potency and decreased toxicity, as well as drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for development of antiviral drugs are described--an empirical strategy and a rational strategy--with several examples of each. Although many compounds have potent antiviral activity in cell culture, only a small fraction of these will go on to become antiviral drugs for use in humans. At this time, only seven synthetic compounds and alpha interferon have been approved by the FDA for therapy of viral infections in humans. None of these approved drugs are without toxicities, however, and hence there is a great need for antiviral drugs with increased potency and decreased toxicity, as well as for drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for the development of antiviral drugs--the empirical and the rational strategies--and their applications and future directions are discussed.

Full text

PDF
216

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Badger J., Minor I., Kremer M. J., Oliveira M. A., Smith T. J., Griffith J. P., Guerin D. M., Krishnaswamy S., Luo M., Rossmann M. G. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Natl Acad Sci U S A. 1988 May;85(10):3304–3308. doi: 10.1073/pnas.85.10.3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Colonno R. J., Condra J. H., Mizutani S., Callahan P. L., Davies M. E., Murcko M. A. Evidence for the direct involvement of the rhinovirus canyon in receptor binding. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5449–5453. doi: 10.1073/pnas.85.15.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cormier J. F., Ogilvie K. K. Synthesis of hexanucleotide analogues containing diisopropylsilyl internucleotide linkages. Nucleic Acids Res. 1988 May 25;16(10):4583–4594. doi: 10.1093/nar/16.10.4583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De Clercq E. Chemotherapeutic approaches to the treatment of the acquired immune deficiency syndrome (AIDS). J Med Chem. 1986 Sep;29(9):1561–1569. doi: 10.1021/jm00159a001. [DOI] [PubMed] [Google Scholar]
  5. Green P. J., Pines O., Inouye M. The role of antisense RNA in gene regulation. Annu Rev Biochem. 1986;55:569–597. doi: 10.1146/annurev.bi.55.070186.003033. [DOI] [PubMed] [Google Scholar]
  6. HITCHINGS G. H., ELION G. B., FALCO E. A., RUSSELL P. B., VANDERWERFF H. Studies on analogs of purines and pyrimidines. Ann N Y Acad Sci. 1950 Jul 7;52(8):1318–1335. doi: 10.1111/j.1749-6632.1950.tb54032.x. [DOI] [PubMed] [Google Scholar]
  7. Hirsch M. S. AIDS commentary. Azidothymidine. J Infect Dis. 1988 Mar;157(3):427–431. doi: 10.1093/infdis/157.3.427. [DOI] [PubMed] [Google Scholar]
  8. Hirsch M. S., Kaplan J. C. Treatment of human immunodeficiency virus infections. Antimicrob Agents Chemother. 1987 Jun;31(6):839–843. doi: 10.1128/aac.31.6.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lemaitre M., Bayard B., Lebleu B. Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site. Proc Natl Acad Sci U S A. 1987 Feb;84(3):648–652. doi: 10.1073/pnas.84.3.648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Loose-Mitchell D. S. Antisense nucleic acids as a potential class of pharmaceutical agents. Trends Pharmacol Sci. 1988 Feb;9(2):45–47. doi: 10.1016/0165-6147(88)90112-5. [DOI] [PubMed] [Google Scholar]
  11. Luo M., Vriend G., Kamer G., Minor I., Arnold E., Rossmann M. G., Boege U., Scraba D. G., Duke G. M., Palmenberg A. C. The atomic structure of Mengo virus at 3.0 A resolution. Science. 1987 Jan 9;235(4785):182–191. doi: 10.1126/science.3026048. [DOI] [PubMed] [Google Scholar]
  12. Matsukura M., Shinozuka K., Zon G., Mitsuya H., Reitz M., Cohen J. S., Broder S. Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7706–7710. doi: 10.1073/pnas.84.21.7706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Miller P. S., Ts'o P. O. A new approach to chemotherapy based on molecular biology and nucleic acid chemistry: Matagen (masking tape for gene expression). Anticancer Drug Des. 1987 Oct;2(2):117–128. [PubMed] [Google Scholar]
  14. Miller P. S., Yano J., Yano E., Carroll C., Jayaraman K., Ts'o P. O. Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates. Biochemistry. 1979 Nov 13;18(23):5134–5143. doi: 10.1021/bi00590a017. [DOI] [PubMed] [Google Scholar]
  15. Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
  16. Moser H. E., Dervan P. B. Sequence-specific cleavage of double helical DNA by triple helix formation. Science. 1987 Oct 30;238(4827):645–650. doi: 10.1126/science.3118463. [DOI] [PubMed] [Google Scholar]
  17. Prusoff W. H., Lin T. S., Zucker M. Potential targets for antiviral chemotherapy. Antiviral Res. 1986 Oct;6(6):311–328. doi: 10.1016/0166-3542(86)90014-8. [DOI] [PubMed] [Google Scholar]
  18. Reines E. D., Gross P. A. Antiviral agents. Med Clin North Am. 1988 May;72(3):691–715. doi: 10.1016/S0025-7125(16)30766-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rossmann M. G. Viral receptors and drug design. Nature. 1988 Jun 2;333(6172):392–393. doi: 10.1038/333392a0. [DOI] [PubMed] [Google Scholar]
  20. Simpson M. V., Chin C. D., Keilbaugh S. A., Lin T. S., Prusoff W. H. Studies on the inhibition of mitochondrial DNA replication by 3'-azido-3'-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Pharmacol. 1989 Apr 1;38(7):1033–1036. doi: 10.1016/0006-2952(89)90245-1. [DOI] [PubMed] [Google Scholar]
  21. Smith C. C., Aurelian L., Reddy M. P., Miller P. S., Ts'o P. O. Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5. Proc Natl Acad Sci U S A. 1986 May;83(9):2787–2791. doi: 10.1073/pnas.83.9.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Smith T. J., Kremer M. J., Luo M., Vriend G., Arnold E., Kamer G., Rossmann M. G., McKinlay M. A., Diana G. D., Otto M. J. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science. 1986 Sep 19;233(4770):1286–1293. doi: 10.1126/science.3018924. [DOI] [PubMed] [Google Scholar]
  23. Stein C. A., Cohen J. S. Oligodeoxynucleotides as inhibitors of gene expression: a review. Cancer Res. 1988 May 15;48(10):2659–2668. [PubMed] [Google Scholar]
  24. Thuong N. T., Asseline U., Roig V., Takasugi M., Hélène C. Oligo(alpha-deoxynucleotide)s covalently linked to intercalating agents: differential binding to ribo- and deoxyribopolynucleotides and stability towards nuclease digestion. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5129–5133. doi: 10.1073/pnas.84.15.5129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. To R. Y., Booth S. C., Neiman P. E. Inhibition of retroviral replication by anti-sense RNA. Mol Cell Biol. 1986 Dec;6(12):4758–4762. doi: 10.1128/mcb.6.12.4758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zamecnik P. C., Goodchild J., Taguchi Y., Sarin P. S. Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4143–4146. doi: 10.1073/pnas.83.12.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zamecnik P. C., Stephenson M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978 Jan;75(1):280–284. doi: 10.1073/pnas.75.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine

RESOURCES