Stapled Peptides with [gamma]-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction

• Published in: Angewandte Chemie International Edition Vol. 55; no. 13; p. 4252
• Main Authors: Speltz, Thomas E, Fanning, Sean W, Mayne, Christopher G, Fowler, Colin, Tajkhorshid, Emad, Greene, Geoffrey L, Moore, Terry W
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 18.03.2016
• Edition: International ed. in English
• Subjects: Estrogens; Peptides
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201510557

"Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the [gamma]-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator2, which interacts with estrogen receptor[alpha]. The best peptide (IC50=89nm) replaces isoleucine689 with an S-[gamma]-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-[gamma]-methyl peptide minimizes the syn-pentane interactions between the [alpha]- and [gamma]-methyl groups.