Stapled Peptides with γ‐Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction

“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 γ‐position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC 50 =89 n m ) replaces isoleucine 689 with an S ‐γ‐methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 n m ). Through X‐ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S ‐γ‐methyl peptide minimizes the syn ‐pentane interactions between the α‐ and γ‐methyl groups.