HIV-1 Accessory Factors as Drug Discovery Targets

Description of projects available to graduate students:
Our group continues to explore the interaction of Src family kinases with Nef, an HIV accessory protein essential for AIDS progression. Nef binds directly to the SH3 domains of three Src family members found in HIV target cells (Hck, Lyn and c-Src), leading to constitutive kinase activation. At the molecular level, we found that the Nef:Hck complex represents a novel active conformation of the kinase, which has important implications for both Src family kinase signal transduction and selective inhibitor discovery. In collaboration with the University of Pittsburgh Drug Discovery Institute, we have completed in vitro and cell-based high-throughput screens of chemical libraries to identify selective inhibitors of the Nef:Hck complex. The screens identified two new classes of compounds with potent anti-HIV activity in vitro. These compounds represent exciting new tools for exploring the role of Nef-SFK signaling in HIV pathogenesis and may represent new leads for anti-HIV drug development. In collaboration with the Department of Structural Biology, we are actively seeking to map the binding site for these small molecule inhibitors within the Nef:Hck complex.

Techniques graduate student will learn:
High-throughput screening, kinase assays, recombinant protein expression and purification, HIV replication assays, flow cytometry