An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein–Protein Interactions

Claire M. Grison, Jennifer A. Miles, Sylvie Robin, Andrew J. Wilson*, David J. Aitken

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein–protein interactions (PPIs). In this work, trans-2-aminocyclobutanecarboxylic acid (tACBC) was used as the key β-amino acid component in the design of α/β/γ-peptides to structurally mimic a native α-helix. Suitably functionalized α/β/γ-peptides assume an α-helix-mimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type α-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.

Original languageEnglish
Pages (from-to)11096-11100
Number of pages5
JournalAngewandte Chemie - International Edition
Volume55
Issue number37
DOIs
Publication statusPublished - 5 Sept 2016

Bibliographical note

Funding Information:
The award of a French MESR doctoral research scholarship (to C.M.G.) is acknowledged. The European Research Council [ERC-PoC 632207], Leverhulme Trust [RPG-2013-065] and The Wellcome Trust [104920/Z/14/Z] are acknowledged for financial support of this research. The authors thank Arnout Kalverda and Gary Thompson for assistance with HSQC experiments and Jean-Pierre Baltaze for help with ROESY experiments.

Publisher Copyright:
© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Keywords

  • foldamers
  • inhibitors
  • peptidomimetics
  • protein–protein interactions
  • α-helix mimetics

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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