Design, Synthesis And Biological Evaluation Of Small Molecules That Inhibit Hiv-1 Entry And Sensitize Hiv-1 Infected Cells To Immune Responses

With over 37 million people living with HIV worldwide and an estimated 2 million new infections reported last year, the need to derive novel strategies aimed not only at protection from, but more importantly at eradication of HIV-1 infection remains a critical worldwide challenge. Our program project aims to develop potent, broadly active small molecule CD4 mimetic compounds (CD4mc) that promote multiple biological responses. While these small molecules were initially optimized for inhibition of HIV-1 entry, recent studies have demonstrated that these small molecule CD4mc synergize with antibodies to control and potentially eradicate HIV-1 infection both by sensitization of viral particles to neutralization and sensitization of HIV-1 infected cells to antibody-dependent cellular cytotoxicity (ADCC). The first part of my thesis describes the development of a late-stage derivatization strategy for the synthesis of 1,2,5,7-tetrasubstituted aminoindane small molecule CD4mc and the corresponding biological evaluation. The second part highlights the discovery and development of a new structural class of small molecule CD4mc with the capacity to elicit ADCC responses that was identified through a high-throughput screen performed by our collaborator. This project focused on efforts both to synthesize a broad set of analogues based on the original HTS hit, utilizing parallel synthetic library design, and to define the structure-activity relationships (SAR) observed. Recent crystallographic studies identified the binding site of this new class of CD4mc, which has led to the design of new, more potent analogues.