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Abstract
Protein-protein interactions (PPIs) are ubiquitous and play a vital role in regulating signal transduction as well as various other fundamental cellular processes. Their dysregulation is implicated in the development of several pathological conditions making them potentially attractive drug targets. However, PPIs have traditionally been dubbed “undruggable” due to their inherent nature making them incompatible with the traditional drug design strategies and approaches. Nonetheless, PPIs provide a novel avenue for the development of PPI disruptors and modulators, not only as potential therapeutics but as molecular tools to dissect and better elucidate the intricacies of cellular signaling. Making mimetics for one of the interacting interfaces involved in mediating a PPI has long been considered a viable strategy for targeting such interactions. PPI interfaces often involve and are stabilized by defined, complementary secondary structures of the interacting proteins. Provided that the structural information is available for the PPI of interest, designing peptides, natural or synthetic, modeled after the structural template provided by the interacting protein interfaces serves as a logical step in developing a modulator. However, excising a peptide out of a parent protein results in the loss of its defined secondary structure due to factors such as backbone solvation and side chain interactions. This increases the overall entropic penalty, making target engagement unfavorable while also making these peptides susceptible to proteolytic degradation. Such native peptides can then be synthetically modified to improve upon all aspects mentioned above. All-hydrocarbon stapling involves strategic placement of synthetic olefinic amino acid residues within the native peptide sequence followed by ring closing metathesis. This leads to macrocyclization of the peptide thus reinforcing its secondary structure, reducing entropic penalty while also making the peptide resistant to proteolytic cleavage.
The goal of this work was to explore the design and development of all-hydrocarbon stapled peptides to develop novel molecular tools to probe and disrupt various intracellular PPIs. This involves stapled peptides that modulate scaffolded, spatiotemporal signaling of Protein Kinase C as well as peptide disruptors designed to target the multiprotein WASF Regulatory Complex implicated in regulating actin cytoskeleton and driving breast cancer metastasis.