Inhibiting EGFR dimerization using triazolyl-bridged dimerization arm mimics

PloS One
Laura E HanoldEileen J Kennedy

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.

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Citations

Feb 3, 2016·Frontiers in Bioengineering and Biotechnology·Andrea GroßJutta Eichler
Apr 5, 2015·Bioorganic & Medicinal Chemistry·Laura E HanoldEileen J Kennedy
Feb 12, 2017·Pharmacology & Therapeutics·Laura E HanoldEileen J Kennedy
Mar 4, 2017·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Yuan TianZigang Li
Sep 5, 2015·Molecular Biology of the Cell·Christopher C ValleyDiane S Lidke
Jul 19, 2016·Expert Review of Proteomics·Rebecca Christine Feiner, Kristian Mark Müller
Mar 28, 2017·The FEBS Journal·Richard BaylissPatrick J McIntyre
Apr 24, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jascha T ManschwetusEileen J Kennedy
Sep 13, 2020·Journal of Experimental & Clinical Cancer Research : CR·Andrew BrennanJody M Mason
Feb 7, 2021·Drug Discovery Today·Léopold ThabaultRaphaël Frédérick
Dec 19, 2020·International Journal of Molecular Sciences·Rebecca C FeinerKristian M Müller
Nov 13, 2020·Reports of Biochemistry & Molecular Biology·Forough Abdollahzadeh, Foroogh Nejatollahi
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Naima AgouramAbdeslem Bentama

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Methods Mentioned

BETA
circular dichroism
Assay
NMR
Fluorescence

Software Mentioned

AmberTools
PyMol
GAFF
GraphPad Prism
acpype
cluster
Cell Sens
hbond
Gromacs
Jasco Spectra Manager

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