Cyclization strategies to stabilize epidermal growth factor receptor dimerization arm mimics
Hanold, Laura Elizabeth
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Protein-protein interactions (PPIs) have critical roles in the regulation of signal transduction in the cell, and the dysregulation of these signaling pathways contributes to various disease states. As such, PPIs offer promising targets for the development of modulators of cell signaling and potential therapeutics. The design of constrained peptides is an attractive strategy for PPI disruption, as these molecules can mimic secondary structures contributing to PPIs. This strategy has primarily been used to target helix-mediated interactions; however, there are significantly fewer reports of peptides disrupting β-loop-mediated PPIs. One extensively studied and therapeutically relevant example of a β-loop-mediated PPI is the epidermal growth factor receptor (EGFR) dimer, which is largely stabilized by a β-loop termed the dimerization arm. Ligand-induced EGFR dimerization leads to activation of the kinase, which promotes signaling pathways involved in proliferation and survival in cancer. As such, disruptors that specifically target the dimerization interface may provide promising probes of EGFR dimerization while also suppressing tumor growth and survival. Thus, the aim of this research is to test highly stable chemical constraints to develop cyclic peptides mimicking the EGFR dimerization arm as potential dimer disruptors. Using selenylsulfide and triazole chemistries, cyclic dimerization arm mimics were developed. Each of these constraints increased the resistance of the peptides to proteolytic degradation while also altering the conformation compared to unconstrained peptides. A 1,4-triazolyl-bridged peptide also demonstrated promise as a molecular probe of EGFR dimerization by disrupting EGFR phosphorylation and dimerization while reducing cell viability. Thus, this panel of constraints enables access to peptides with variety of conformations, increased stability, and the potential to disrupt dimerization. These approaches may have broad applications in the design of constrained peptides for the disruption of alternative β-loop mediated interactions. Furthermore, beyond the scope of this project, additional testing and optimization of these peptides and their analogs may lead to the development of potential anticancer therapeutics targeting EGFR dimerization.