A NOVEL TARGET FOR DEVELOPING ANTI-HIV INHIBITORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The global HIV epidemic continues to expand exceeding previous predictions and became one of the deadliest epidemics in human history. The high prevalence of HIV infection in the African-American women requests the new medical intervention toward eliminating women's health disparities in HIV/AIDS. Considering the continual emergence of HIV strains that are resistant to currently approved anti-HIV drugs, the discovery and development of new anti-HIV drugs with novel antiviral mechanisms and targets are urgently need. The long-term objective of this application is to develop a novel class of anti-HIV drugs representing novel chemical entities targeting late stages of the HIV-1 replication cycle. Our recent studies demonstrate a novel protein-protein interaction between HIV-1 Gag and host filamin A (FLNa), which is involved in late stages of the HIV-1 replication cycle in a productive manner. Disruption of the interaction redistributes Gag subcellular localization and inhibits particle release. These data suggest that the Gag-FLNa interaction could be developed as targets for HIV therapeutics. We hypothesize that small synthetic peptides, containing the binding site of FLNa for Gag, might block specifically the Gag-FLNa interaction resulting in the impaired virus assembly and release. Experiments designed in this application will be performed to test this central hypothesis by defining the biochemical basis of the Gag-FLNa interaction, identifying peptide candidates to disrupt the interaction in vitro, and characterizing the effect of peptide candidates on virus assembly and release. Our studies will provide important new information regarding retrovirus-host interactions. More importantly, our studies have a high potential impact to develop novel anti-retroviral drugs with novel targets. This application will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the binding site of FLNa required for the interaction. Specific Aim 2: To identify peptide candidates to specifically block the interaction in vitro. Specific Aim 3: To examine the effect of peptide candidates on virus assembly and release.