Cell-surface receptors and intracellular regulatory proteins are preeminent mediators of cellular signaling as these proteins are involved in a host of interactions and pathways. Therefore, various stages of their signaling cycles provide unique opportunities for therapeutic intervention. This project presents computational studies integrated with experimental data to resolve the mechanisms of recognition of novel peptide mimetics and analogues targeting extracellular domains of receptor proteins of the insulin family and small-molecules targeting intracellular protein-protein interactions in regulatory proteins of the G-protein coupled receptor (GPCR) family. The proposed studies are timely in that several recent structural studies have revealed the binding modes of the native hormone insulin and homologous growth factor peptides and we have developed dynamics-based computational approaches that have opened the avenues for designing novel peptide-based agonists and antagonists. Toward this direction are our proposed studies of three classes of peptides: (1) synthetic insulin mimetics, (2) viral-insulin-like peptides (VILPs), and insulin-like peptides from cone snail venom. Our second research direction aims to develop small-molecule inhibitors targeting a key intracellular protein-protein interaction between regulators of G-protein signaling (RGS) proteins and the alpha-subunits of G-proteins. As opposed to the conventional approach of directly targeting the protein-protein interface, we propose to target allosteric sites on RGS proteins to inhibit the protein-protein interaction. Through preliminary studies on a model protein, we have shown that allosteric control and targeting is feasible and through this project we propose to broaden the scope of these promising studies to new protein targets involved in cancer and visual signaling. Overall, we anticipate that the mechanistic paradigms emerging from these studies will have broader applicability to other protein families and will facilitate the design of novel therapeutic strategies.
Recognizing the need to address wide-spread metabolic (e.g. diabetes), growth (e.g. cancer), neurological, and visual disorders, this research will elucidate the molecular basis of interactions between peptides/small-molecules and signaling proteins that participate in protein-protein interactions. Characterization of these binding modes and mechanisms will accelerate the pace of discovery for designing novel therapeutic approaches targeting these proteins.
