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Stapled Peptides with γ‐Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction
Author(s) -
Speltz Thomas E.,
Fanning Sean W.,
Mayne Christopher G.,
Fowler Colin,
Tajkhorshid Emad,
Greene Geoffrey L.,
Moore Terry W.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201510557
Subject(s) - isoleucine , chemistry , amino acid , peptide , coactivator , stereochemistry , steroid , estrogen receptor , leucine , biochemistry , biology , hormone , transcription factor , gene , genetics , cancer , breast cancer
Abstract “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.

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