Effects of replacement and addition of an amino acid contained in a cyclic peptide corresponding to a β-hairpin loop sequence of human EGF receptor.

Effects of replacement and addition of an amino acid in a cyclic decapeptide 1 (cyclic-CYNPTTYQMC) for inhibitory activity to dimerization of human epidermal growth factor receptor (EGFR) were examined. By alanine scanning of 1 corresponding to the arm structure (residues 246-254) of a β-hairpin loop sequence (residues 242-259) of EGFR, it was confirmed that replacement of any amino acid in the loop structure lowered the dimerization inhibitory activity of 1. Among the residues examined, Tyr at position 246 and Thr at 250 were found to be crucial for dimer formation. Addition of an amino acid to the N-terminus of 1 also affected the dimerization inhibitory activity. Addition of an amino acid containing a moderately hydrophilic side-chain increased the inhibitory activity. In contrast, an intramolecular hydrogen bond of 1 is not thought to be crucial for holding the dimer structure on the basis of the dimerization inhibitory activities of N-methylated analogues of 1. These results will be useful for the design and evaluation of a potent dimerization inhibitor as an anti-proliferation agent. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.