Principal Investigator/Program Director (Last, First, Middle): Chaiken, IfWJn M DESCRIPTION: The main objective of Core B is to provide protein technology services, including protein reagents, ligand binding analyses and methods development, to support investigation of structure-based antagonism of human immunodeficiency virus -1 (HIV-1) entry. HIV-1 infection is initiated by entry of the virus into host cells. Interaction of HIV-1 gp120 envelope protein with host cell receptor, CD4, followed by binding to a co-receptor, most commonly the chemokine receptors CCR5 or CXCR4, are crucial steps in the process of viral entry. The overall goal of this Program Project is to identify agents that will antagonize these protein-binding events. Candidate inhibitors of gp120 interactions will be generated by various members of the Program Project team, in particular, Project 1, Structure analysis of HIV-1 entry inhibition, Project 2, Peptide-inspired competitive and allosteric inhibitors of HIV-1 entry and Project 3, Discovery and synthesis of small-molecule CD4-gp120 antagonists. In order to analyze the efficacy and mechanisms of action of these candidate inhibitors, protein reagents will be required by the above projects, in coordination with Project 4, Assembly and inhibition thermodynamics, and Project 5, Structure-based antagonism of HIV-1 envelope function in cell entry. Furthermore, SPR-based screening of these inhibitor candidates with gp120s from multiple subtypes, both in direct binding and functional assays, will help prioritize thermodynamic investigations, while also aiding the molecular interpretation of biological assays. The data generated through the screening assays also will help test the hypotheses of inhibitor interaction mechanisms developed in Core A, Computational modeling.
The specific aims of Core B are to: (1) Produce, purify and validate protein reagents required by Program Project members, including envelope monomers and trimers from diverse clades of HIV-1, soluble constructs of HIV-1 receptors and antibodies for both purification and characterization studies. (2) Screen kinetic interaction properties of gp120 antagonist candidates for direct interaction and effector activity profiles, which will contribute information that will be invaluable in the compound prioritization process. (3) Develop, validate and implement new technologies for recombinant protein expression, purification and binding assays to serve evolving needs of the Program Project. Transfer new technologies to P01 projects to further enable mechanistic and antagonist design investigations. Overall, this Core will provide Project Team members with a central resource that will both produce and supply high quality protein reagents, in addition to screening candidate antiviral molecules and developing novel assay systems for the investigation of these compounds. The work of Core B will adapt its activities in these areas to the evolving needs of the Projects in order to support investigations of HIV-1 entry antagonism and structure- based antagonist design.
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