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Title: 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]; ORCiD logo [1]
  1. Univ. of Illinois, Chicago, IL (United States)
  2. Univ. of Illinois at Urbana-Champaign, IL (United States)
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“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)
Grant/Contract Number:
P41-GM104601; T32 AT007533
OSTI ID:
1274765
Journal Information:
Angewandte Chemie (International Edition), Vol. 55, Issue 13; ISSN 1433-7851
Publisher:
WileyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 62 works
Citation information provided by
Web of Science

References (30)

An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides journal June 2000
Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors: BEYOND THE LIGAND-BINDING POCKET journal November 2012
Crystal Structures of Stapled and Hydrogen Bond Surrogate Peptides Targeting a Fully Buried Protein–Helix Interaction journal August 2014
Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes journal June 2015
Scalable molecular dynamics with NAMD journal January 2005
D538G Mutation in Estrogen Receptor- : A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer journal November 2013
A signature motif in transcriptional co-activators mediates binding to nuclear receptors journal June 1997
Makrocyclische Peptide mit dem Zielprotein angepassten Kohlenwasserstoffbrücken: Inhibitoren einer pathogenen Protein-Protein-Wechselwirkung journal February 2014
Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of .alpha.-substituted carboxylic acid derivatives journal March 1982
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer journal June 2010
Structure of the Stapled p53 Peptide Bound to Mdm2 journal December 2011
NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses journal March 2008
Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy journal August 2013
Modulating protein–protein interactions: the potential of peptides journal January 2015
Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts journal September 2013
Minireview: Not Picking Pockets: Nuclear Receptor Alternate-Site Modulators (NRAMs) journal April 2010
Hydrocarbon Stapled Peptides as Modulators of Biological Function journal March 2015
A Set of Time-Resolved Fluorescence Resonance Energy Transfer Assays for the Discovery of Inhibitors of Estrogen Receptor-Coactivator Binding journal February 2009
Strukturbasierte Entwicklung von Protein-Protein-Interaktionsinhibitoren: Stabilisierung und Nachahmung von Peptidliganden journal June 2015
Towards understanding cell penetration by stapled peptides journal January 2015
Activating ESR1 mutations in hormone-resistant metastatic breast cancer journal November 2013
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer journal November 2013
Proline Primed Helix Length as a Modulator of the Nuclear Receptor–Coactivator Interaction journal March 2013
Synthesis of all-hydrocarbon stapled α-helical peptides by ring-closing olefin metathesis journal May 2011
Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors α and β journal December 1999
Enantioselective synthesis of non-proteinogenic amino acids via metallated bis-lactim ethers of 2,5-diketopiperazines journal January 1983
Design and Structure of Stapled Peptides Binding to Estrogen Receptors journal June 2011
VMD: Visual molecular dynamics journal February 1996
Constrained Peptides with Target-Adapted Cross-Links as Inhibitors of a Pathogenic Protein-Protein Interaction journal February 2014
Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts text January 2013

Cited By (16)

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
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
An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide journal May 2016

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Related Subjects

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