DRUG DESIGN CYCLE TARGETED TO RETROVIRAL PROTEASES

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The goal of this Program is to develop mature tools to aid in the drug design cycle for anti-retroviral agents. The program consists of five integrated parts: 1. Computational methods for docking active-site ligands (inhibitors), and for elaboration and refined design of inhibitor lead compounds; 2. design and chemical synthesis of retroviral protease inhibitors using new chemical approaches; 3. Xray crystallographic studies of the feline immunodeficiency virus (FIV PR) and inhibitor complexes; 4. Protein chemical studies of the FIV PR using total chemical synthesis; 5. Molecular biology/virology of the FIV system. Fundamental studies of the structural biology of the retroviral protease of the feline immunodeficiency virus will be undertaken in the context of developing novel tools for targeted drug design and with the ultimate goal of increasing our understanding of inhibitor design for this important class of retroviral enzyme. The human immunodeficiency virus-1 (HIV-1) PR is essential to the replication of the virus, and consequently is the target of major drug design programs worldwide. Based on our own past work and the work of others there are already indications of unique structural and mechanistic features of HIV-1 PR compared with cell-encoded aspartyl proteinases that could serve as a basis for the design of a class of retroviral-selective inhibitors, as candidate AIDS therapeutics. The purpose of this Program is to extend these studies to a more directly testable model system, the FIV PR, and confirm the reality and generality of these features. the fundamental knowledge resulting from these studies of FIV PR will be important for the understanding of related clinically- relevant enzymes, such as the HIV-1 and other retroviral proteases, and cell-encoded aspartyl proteinases such as renin.