Mono-substituted Hydrocarbon Diastereomer Combinations Reveal Stapled Peptides with High Structural Fidelity

Fergus S Mcwhinnie, Kristel Sepp, Charlotte Wilson, Tilo Kunath, Ted R Hupp, Terry S Baker, Douglas R Houston, Alison Nicola Hulme

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 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
Original languageEnglish
JournalChemistry - A European Journal
Early online date21 Dec 2017
Publication statusE-pub ahead of print - 21 Dec 2017


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