title: Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy and UI Cancer Center, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL, 60612, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Speltz
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Sean W
authors.initials: SW
authors.lastname: Fanning
authors.affiliation: Beckman Institute for Advanced Science and Technology, The University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Fowler
authors.affiliation: Beckman Institute for Advanced Science and Technology, The University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy and UI Cancer Center, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL, 60612, USA. twmoore@uic.edu.
authors.forename: Terry W
authors.identifier: http://orcid.org/0000-0002-5410-306X
authors.initials: TW
authors.lastname: Moore
mesh_terms: D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D006838:Hydrocarbons / Q000737:chemistry*; D008745:Methylation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000737:chemistry*
chemical_list: D006838:Hydrocarbons; D010455:Peptides; D011960:Receptors, Estrogen
keywords: amino acids; conformational analysis; peptides; peptidomimetics; receptors