STRUCTURAL STUDIES OF FIV PROTEASE INHIBITOR COMPLEXES

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We will use X-ray crystallography to study the molecular structure of the Feline Immunodeficiency Virus protease (FIV PR) as the basis for a program aimed at developing the tools for structure and mechanism based drug design. Understanding of the molecular structure of the FIV PR in that context will contribute to the development of AIDS therapeutics based on inhibiting the HIV-1 PR. First, the molecular structure of FIV PR will be worked out by modelling based on the structures of RSV PR and HIV-1 PR determined in our laboratory. Such a model will be useful in experimentally determining the X-ray crystallographic structure of the FIV PR, and for preliminary inhibitor design. The crystal structure of FIV PR will be determined, unliganded and as a complex with substrate-based inhibitors. This information will be used in an initial round of inhibitor/drug design. Inhibitors selected from this first round of design will be used in further studies of the FIV PR-inhibitor complex. Selected PR-inhibitor complexes will be determined to very high resolution to provide the basis for quantitative understanding of enzyme-ligand interactions. Refined inhibitor design and improvement of the design tools will be based on data obtained in this iterative fashion. The FIV PR structures obtained will be compared and contrasted with the RSV PR and HIV-1 PR structures to draw general inferences concerning the structural origins of the properties of these important retroviral enzymes.