TCB Publications - Abstract

Thomas E. Speltz, Sean W. Fanning, Christopher G. Mayne, Colin Fowler, Emad Tajkhorshid, Geoffrey L. Greene, and Terry W. Moore. Stapled peptides with γ-methylated hydrocarbon chains for the estrogen receptor/coactivator interaction. Angewandte Chemie - International Edition in English, 55:4252-4255, 2016.

SPEL2016-ET “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 coactivator 2, which interacts with estrogen receptor $\alpha$. The best peptide (IC$_{50}$=89 nm) replaces isoleucine 689 with an S-$\gamma$-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). 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.

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