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

Journal Article · · Angewandte Chemie (International Edition)
 [1];  [1];  [2];  [1];  [2];  [1];  [1]
  1. Univ. of Illinois, Chicago, IL (United States)
  2. Univ. of Illinois at Urbana-Champaign, IL (United States)
+ Show Author Affiliations
“Stapled” peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, in this work 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
American Association of Colleges of Pharmacy; Searle Funds at The Chicago Community Trust; National Institutes of Health (NIH); National Center for Complementary and Integrative Health; National Science Foundation (NSF)
OSTI ID:
1274765
Journal Information:
Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Journal Issue: 13 Vol. 55; ISSN 1433-7851
Publisher:
WileyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide journal May 2016
An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide journal May 2016
New Modalities for Challenging Targets in Drug Discovery journal July 2017
Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions journal August 2017
Locking Interconversion of Aromatic Oligoamide Foldamers by Intramolecular Side-chain Crosslinking: toward Absolute Control of Helicity in Synthetic Aromatic Foldamers journal March 2017
Tuning the Binding Affinity and Selectivity of Perfluoroaryl‐Stapled Peptides by Cysteine‐Editing journal November 2018
Metathesis-Based Stapling of a Pyridine-Acetylene-Phenol Oligomer Having Alkenyl Side Chains after Intermolecular Templation by Native Saccharides: Metathesis-Based Stapling of a Pyridine-Acetylene-Phenol Oligomer Having Alkenyl Side Chains after Intermolecular Templation by Native Saccharides journal June 2018
Bent into shape: Folded peptides to mimic protein structure and modulate protein function journal January 2020
Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity journal December 2016
An in-tether sulfilimine chiral center induces helicity in short peptides journal January 2016
A precisely positioned chiral center in an i, i + 7 tether modulates the helicity of the backbone peptide journal January 2017
N terminal N -methylation modulates chiral centre induced helical (CIH) peptides’ biophysical properties journal January 2018
A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway journal January 2017
Reversible stapling of unprotected peptides via chemoselective methionine bis-alkylation/dealkylation journal January 2018
A siRNA-induced peptide co-assembly system as a peptide-based siRNA nanocarrier for cancer therapy journal January 2018
Computational biochemical investigation of the binding energy interactions between an estrogen receptor and its agonists journal January 2018
A “cross-stitched” peptide with improved helicity and proteolytic stability journal January 2018
Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design journal January 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
amino acids
conformational analysis
peptides
peptidomimetics
receptors