Identification of Small-Molecule Inhibitors of Protein-Protein Interactions

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DESCRIPTION (provided by applicant): Recent high-throughput proteomic studies that identify protein complexes and/or binary interactions have not only produced a wealth of information, but have underscored the ubiquitous and fundamental role protein-protein interactions (PPIs) play in cell biology. In part as a consequence of these studies, PPIs are rapidly gaining acceptance as promising drug targets with tremendous therapeutic potential, however very little is known about the structural features that render a PPI "druggable", or the chemical characteristics that constitute an effective inhibitor of a PPI. With the exception of a small number of success stories, target-based screening strategies have done poorly at identifying PPI inhibitors. This proposal describes a novel approach to developing small-molecule inhibitors of PPIs. Our approach merges molecular bar-code technology with two established methodologies for detecting PPIs in vivo; the yeast two-hybrid (Y2H) system and the protein complementation assay (PCA). Both Y2H and PCA are robust methods that detect distinct types of PPIs, and in this sense are complementary. Their potential utility in screening for, and uncovering inhibitors of PPIs has been proposed previously. By leveraging the molecular bar-code technology, in which the Stanford Genome Technology Center (SGTC) has played a pioneering role in developing, as well as the extensive chemical screening infrastructure currently in place at the SGTC, we propose to screen hundreds of disease-associated human PPIs with ~20,000 diverse chemical compounds. These experiments will generate a massive dataset (representing millions of individual tests) that will be an unparalleled resource for addressing key questions regarding the druggability of PPIs, and the chemical features that define PPI inhibitors. Specific inhibitors identified by these screens could also be valuable biological tools for precisely dissecting the function of the associated proteins in cultured human cell lines. Furthermore, while they will not likely posses the pharmacokinetic or pharmacodynamic properties required of a therapeutic agent, these inhibitors could serve as promising starting points for new drugs. PUBLIC HEALTH RELEVANCE: Protein-protein interactions (PPIs) are a promising class of drug targets with wide-spread therapeutic potential. This proposal describes a unique merging of existing technologies with the goal of identifying novel chemical inhibitors of PPIs. These inhibitors could be valuable tools for studying biology and/or serve as starting points for developing new drugs.