Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Monday Speaker Abstracts

Novel Drug Leads: Highly Parallel Screening of Disordered Peptide Motifs for Phenotypic Effects in Cells Philip Kim. University of Toronto, Toronto, ON, Canada Intrinsically disordered (ID) peptides/proteins have crucial roles in the control of cell growth and proliferation and numerous disordered proteins are associated with human diseases such as cancer and immunodeficiency disease. In particular, disordered regions harbour numerous short peptide regions (known as linear motifs) that often function as binding sites. Such motifs mediate a large fraction of protein-protein interactions, especially in signalling, and should thus be good targets for therapeutic intervention. Although numerous studies have attempted to develop potential therapeutic peptides for decades, canonical small-scale screens make it difficult to generate effective and selective anti-tumor peptides. Here, we develop a high-throughput human peptide library screen for peptides inhibiting tumor cell growth. About 400 unique peptide sequences were isolated that exhibited anti-proliferative effects. We observed that these peptides can directly inhibit cancer cell growth without affecting normal cells (targeted therapy) and we identified the protein-protein interaction targets of our top peptides. Using a number of orthogonal experimental techniques, we confirmed that the disruption of these interactions is their likely mode of action, thus identifying novel putative (and known) anti-apoptotic interactions as well as their inhibitors. The identified interactions are ideal new targets for therapeutic intervention while our peptides serve as potential lead compounds. We thus demonstrate that our high-throughput human peptide screen can be a valuable tool to develop novel anti-cancer drugs. Furthermore, our technology can be a powerful means to elucidate the roles of the multitude of disordered peptide motifs.

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