Hanold Laura E, Oruganty Krishnadev, Ton Norman T, Beedle Aaron M, Kannan Natarajan, Kennedy Eileen J
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
PLoS One. 2015 Mar 19;10(3):e0118796. doi: 10.1371/journal.pone.0118796. eCollection 2015.
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.
表皮生长因子受体（EGFR）在多种癌症中过度表达，是多种靶向治疗的焦点。在此，我们报告了基于肽的化合物的设计，这些化合物模拟EGFR二聚化臂并抑制EGFR的变构激活。这些肽经过修饰，在肽链之间含有一个三唑桥，以限制EGFR二聚化臂β-环。在本研究中，我们证明这些肽比未修饰的肽序列具有显著提高的蛋白水解稳定性，并且它们的抑制作用取决于亚甲基单元的数量和引入的三唑桥的方向。我们鉴定出一种肽EDA2，它可下调受体磷酸化和二聚化，并降低细胞活力。这是靶向EGFR二聚化界面的具有生物活性的三唑桥肽有效下调EGFR激活的首个实例。
