Stapled Peptides with γ‐Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction. (1st March 2016)

• Record Type: Journal Article
• Authors: Speltz, Thomas E.; Fanning, Sean W.; Mayne, Christopher G.; Fowler, Colin; Tajkhorshid, Emad; Greene, Geoffrey L.; Moore, Terry W.
• Is Part Of: Angewandte Chemie. Volume 128:Number 13(2016)
• Page Start: 4324
• Page End: 4327
• Publication Date: 2016-03-01
• Subjects: Aminosäuren -- Konformationsanalyse -- Peptide -- Peptidmimetika -- Rezeptoren; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201510557
• Languages: English
• ISSNs: 0044-8249

Abstract

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 (IC50 =89 nm ) replaces isoleucine 689 with an S ‐γ‐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 ‐γ‐methyl peptide minimizes the syn ‐pentane interactions between the α‐ and γ‐methyl groups.