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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