title: Inhibiting EGFR dimerization using triazolyl-bridged dimerization arm mimics.
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.
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors: Laura E
authors: LE
authors: Hanold
authors: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors: Krishnadev
authors: K
authors: Oruganty
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors: Norman T
authors: NT
authors: Ton
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors: Aaron M
authors: AM
authors: Beedle
authors: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors: Natarajan
authors: N
authors: Kannan
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors: Eileen J
authors: EJ
authors: Kennedy
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology*; D002277:Carcinoma / Q000378:metabolism*; D019281:Dimerization; D053331:Ectodysplasins / Q000096:biosynthesis* / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015202:Protein Engineering / Q000379:methods*; D014230:Triazoles / Q000737:chemistry
chemical_list: D053331:Ectodysplasins; D014230:Triazoles; D066246:ErbB Receptors