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Document XVI. Perspective Page 70 Substantial progress has been made in understanding the structure and function of HIV-1 RT and in the development of anti-HIV-1 inhibitors. However, the genetic flexibility of HIV-1 will continue to make development of a truly effective antiviral therapy for AIDS an exceptionally difficult task. We are beginning to understand how to circumvent drug resistance. The accumulated evidence has shown that the ability of the virus to develop drug resistance is limited and that the drug-resistant viral variants are less efficient than the wild-type virus. If the selection pressure provided by antiviral drugs makes the virus pay a sufficiently high price, then the viral load can be decreased and there will be a measurable clinical benefit. Based on a better understanding of the structure-function relationships of HIV-1 RT, we are now coming to grips with the mechanisms of polymerization, drug inhibition, and drug resistance. This information should make it possible to develop new or improved HIV-1 RT inhibitors that have different properties and provoke different patterns of drug-resistance mutations. Though it is likely that there will be no single drug which would be effective against all HIV-1 variants, we have reasons to believe that new or improved drugs or, more likely, new drug combinations, will be designed that are broadly effective against all of the HIV-1 variants that can grow efficiently. Detailed analysis of the conformational changes among the various HIV-1 RT structures may reveal additional sites (in addition to the currently known NRTI- and NNRTI-binding sites) for binding new inhibitors able to interfere with the polymerization and/or the flexibility of the enzyme required for its activity. The considerable physical and genetic flexibility of HIV-1 RT suggests that more effective anti-RT drugs should be designed to target the conserved portions of HIV-1 RT that the virus cannot easily afford to change. Such conserved elements can be identified by comparing the sequences of RTs from different retroviruses; the functions and relative importance of these conserved elements can be determined by mutagenesis and biochemical and structural analyses. It is our hope that application of structure-based drug design strategies may aid in the development of novel HIV-1 RT inhibitors for a more effective treatment of HIV-1 infection. Acknowledgments We thank the other members of the Arnold and Hughes laboratories and our collaborators for their helpful discussions and assistance, including Koen Andries, Gail Ferstandig Arnold, Paul Boyer, Arthur Clark, Jr., Paul Janssen, Jörg-Peter Kleim, Luc Koymans, Tack Kuntz, Karen Lentz, Chris Michejda, Henri Moereels, Manfred Roesner, Marilyn Kroeger Smith, Rick Smith, Jr., and http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_70.html [4/5/2004 4:50:51 PM]
Document Chris Tantillo. The work in Edward Arnold's laboratory has been supported by Janssen Research Foundation and NIH grants (AI 27690 and AI 36144). Research in Stephen Hughes' laboratory is sponsored in part by the National Cancer Institute, DHHS, under contract with ABL, and by NIGMS. References 1. Goff SP. Retroviral reverse transcriptase: synthesis, structure, and function. J Acquired Immune Deficiency Syndromes 1990; 3:817–831. Page 71 2. Jacobo-Molina A, Arnold E. HIV reverse transcriptase structure-function relationships. Biochemistry 1991; 30:6351–6361. 3. Whitcomb JM, Hughes SH. Retroviral reverse transcription and integration: progress and problems. Ann Rev Cell Biol 1992; 8:275–306. 4. Le Grice SFJ. Human immunodeficiency virus reverse transcriptase. In: Skalka AM, Goff SP, eds. Reverse Transcriptase. Plainview, New York: Cold Spring Harbor Laboratory Press, 1993:163–191. 5. De Clercq E. Toward improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infections. J Med Chem 1995; 38:2491–2517. 6. De Clercq E. HIV inhibitors targeted at the reverse transcriptase. AIDS Res Human Retroviruses 1992; 8:119–134. 7. Larder BA. Inhibitors of HIV reverse transcriptase as antiviral agents and drug resistance. In: Skalka AM, Goff SP, eds. Reverse Transcriptase. Plainview, New York: Cold Spring Harbor Laboratory Press, 1993:205–222. 8. St. Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991; 253:1557–1559. 9. Richman DD. Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrob Agents Chemother 1993; 37:1207–1213. 10. Schinazi RF. Competitive inhibitors of human immunodeficiency virus reverse transcriptase. Perspectives in Drug Discovery and Design 1993; 1:151–180. 11. De Clercq E. HIV resistance to reverse transcriptase inhibitors. Biochem Pharmacol 1994; 47:155–169. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_71.html (1 of 2) [4/5/2004 4:50:53 PM]
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Document [Protease targets] serinyl
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