STRUCTURE-BASED CD4-GP120 ANTAGONISM

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The central objective of this research is to use the structure of the gp120/CD4 complex and structure-based mimetics to design antagonists of the interaction of human cells with HIV-1, the human immunodeficiency virus responsible for AIDS. T-cell docking and entry by HIV-1, a major route of cell infection in AIDS, is driven by specific recognition of the T-cell surface protein CD4 by the HIV envelope protein gp120. The crystallographic structure of CD4 is known, and that of its complex with gp120 is close at hand. Structural components in both protein partners have been identified which are proposed to play key roles in CD4-gp120 recognition. The advancing high resolution structural understanding of the protein participants in virus-cell recognition together with the advancing technology of mimetics design now make it possible to combine structure determination, modeling, miniprotein engineering and organic synthesis to design new antagonist for AIDS. The specific aims of this proposal are as follows: (1) to identify binding sites in the CD4-gp120 interface by computational modeling of existing high resolution structures: (2) to transplant CD4 and gp120 binding site components into conformationally constrained miniprotein constructions by recombinant DNA and chemical approaches to obtain miniprotein mimetics and to use these to define the minimal structural information of the gp120 CD4 binding sites needed for stable interaction; (3) to utilize key structural elements, as determined from modeling of the high resolution structure and subsequently miniprotein mimetics, to design small molecule CD4 and/or gp120 antagonists; (4) to identify novel inhibitors of gp120/CD4, to augment the rational design efforts, by screening compounds banks and by synthesizing constrained peptide and semipeptide helix, gamma-turn and beta-turn mimetic libraries. Overall, this project will yield miniprotein and organic synthetic technologies for protein mimetics constructions, an advanced definition of the key structural elements at the interface of the CD4-gp120 complex and new drug candidates for AIDS. Long term, the mimetics strategies derived here will be useful to design antagonists of other protein-protein interactions important in AIDS, such as the gp41-gp120 and chemokine receptor interactions, that also are associated with human cell - HIV-1 docking and viral entry.