This proposal will focus on the use of structural biology to aid in the development of drugs that can interfere in a specific manner with protein products of the human immunodeficiency virus (HIV) genome. Since HIV is the etiological agent implicated in Acquired Immunodeficiency Syndrome (AIDS), it is hoped that these drugs will cure or at least arrest the symptoms of AIDS. Finding a cure for AIDS is an extremely urgent health priority for the world. However, it can be anticipated that the methodologies developed in this AIDS-targeted project could lay the foundations for the development of other anti-viral agents that inevitably will evolve in the future to plague mankind. Inhibitors will be developed toward several HIV-1 proteins: the reverse transcriptase, the protease, the integrase and the ribonuclease H activity of the reverse transcriptase. Recombinant methods for viral protein production are being developed. These proteins, as well as viral proteins obtained from external sources, as appropriate, will be highly purified, crystallized and subjected to X-ray diffraction analysis. The emerging structures will be modeled using computer graphics, and potential inhibitors will in turn be modeled into the structures using molecular dynamics, molecular mechanics and quantum mechanics. Candidate inhibitors will be synthesized, tested with enzyme systems, and sometimes co-crystallized with the enzyme for further structural analysis. Comparisons will be made with regard to their efficacy with cellular enzymes as well as with corresponding enzymes obtained from HIV-2 and simian immunodeficiency virus (SIV). Ideas for even more potent and selective inhibitors should then emerge. Site-directed- mutagenesis will be used to refine notions about which groups on the enzyme are involved in the inhibitor process. Both ex vivo and in vivo anti-viral testing will be performed with some of the more promising compounds.
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