Title
Inhibiting EGFR Dimerization Using Triazolyl-Bridged Dimerization Arm Mimics
Author
Laura E. Hanold, Krishnadev Oruganty, Norman T. Ton, Aaron M. Beedle, Natarajan Kannan, Eileen J. Kennedy
Year
2015
Journal
PLoS ONE
Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in multiple carcinomas and is the focus of a variety of targeted therapies. Here we report the design of peptide-based compounds that mimic the EGFR dimerization arm and inhibit allosteric activation of EGFR. These peptides are modified to contain a triazolyl bridge between the peptide strands to constrain the EGFR dimerization arm β-loop. In this study, we demonstrate that these peptides have significantly improved proteolytic stability over the non-modified peptide sequence, and their inhibitory effects are dependent on the number of the methylene units and orientation of the introduced triazolyl bridge. We identified a peptide, EDA2, which downregulates receptor phosphorylation and dimerization and reduces cell viability. This is the first example of a biologically active triazolyl-bridged peptide targeting the EGFR dimerization interface that effectively downregulates EGFR activation.
Instrument
J-710
Keywords
Circular dichroism, Secondary structure, Chemical stability, Biochemistry