Disrupting protein-protein interactions in multi-subunit enzymes is currently an underutilizes mode of inhibition. This proposal seeks to answer fundamental questions concerning the chemistry and biology of disrupting protein-protein interactions, and utilizes dimeric HIV protease and integrase as templates to address the questions. Specific Questions to be Addressed Protease Inhibition Based on our current model of binding, can we identify modifications that will increase inhibitor affinity for an HIV protease monomer? How potent an inhibitor is needed to shift the dimerization equilibrium of HIV protease and effectively reduce HIV maturation? What are the structural and thermodynamic effects of inhibvitor5 modifications on the protease monomer/inhibitor complex? Integrase Inhibition How general is the approach developed for dimerization inhibition of HIV protease, can it be applied to the inhibition of a structurally different protein such as HIV integrase?
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