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Mono‐Substituted Hydrocarbon Diastereomer Combinations Reveal Stapled Peptides with High Structural Fidelity
Author(s) -
McWhinnie Fergus S.,
Sepp Kristel,
Wilson Charlotte,
Kunath Tilo,
Hupp Ted R.,
Baker Terry S.,
Houston Douglas R.,
Hulme Alison N.
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201705983
Subject(s) - diastereomer , circular dichroism , peptide , chemistry , protein structure , protein data bank (rcsb pdb) , stereochemistry , helicity , crystallography , biochemistry , physics , particle physics
Modified peptides, such as stapled peptides, which replicate the structure of α‐helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution‐phase models for the optimised peptides were generated using NMR‐derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.