The continued structure-based development of inhibitors of key proteins of the human immunodeficiency virus (HIV) and of two organisms responsible for HIV-related opportunistic infections is proposed. Despite major advances in the treatment of acquired immunodeficiency syndrome (AIDS), it remains a major threat to the public health. Furthermore, the widespread appearance of resistance to antibacterial and antiviral drugs and the escalating costs of drug discovery and health care make the development of more rapid and efficient drug discovery methods imperative. Three HIV proteins, integrase, Rev, and Tat, are to be targeted for inhibitor development, and the mechanism of resistance to inhibitors of the HIV-1 protease is to be investigated. In addition, two AIDS-related opportunistic infections, Kasposi's sarcoma and drug-resistant tuberculosis, will be targeted. Discovery efforts will focus on (a) the protease of HHVS, the virus responsible for Kaposi's sarcoma, (b) the Mycobacterium tuberculosis alkylhydroperoxidases AhpC and AhpD that compensate for loss of the KatG peroxidase in isoniazid resistance, and (c) EtaA, the M. tuberculosis flavoprotein that activates ethionamide. The development of inhibitors of KasA-AcpM, one of the ultimate targets of activated isoniazid and ethionamide, is proposed. The proteins required for these studies are to be produced by recombinant methods and purified, crystallized, and subjected to X-ray diffraction analysis. Mechanistic studies of the less well characterized enzyme targets will be carried out to obtain the information required for the design of reversible and irreversible inhibitors. Structural and mechanistic information will be used in conjunction with computational methods to identify potential inhibitors. The inhibitor candidates will be synthesized, assayed with isolated enzymes, and in some cases co-crystallized with the enzymes for structural analysis. Inhibitor optimization will be assisted by computational approaches, and the improvement of such approaches for the discovery and optimization of drug candidates is a further goal of this research program. Promising drug candidates will be evaluated in cell culture and in vivo. This broad, structure-based attack on HIV and two important opportunistic infections should produce fundamental knowledge relevant to the functions of the proteins investigated, to our understanding of drug resistance, to the design of drugs for infectious agents, and to useful drug leads for AIDS.
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