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

Angew Chem Int Ed Engl. 2016 Sep 5;55(37):11096-100. doi: 10.1002/anie.201604517. Epub 2016 Jul 28.

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.

Keywords: foldamers; inhibitors; peptidomimetics; protein-protein interactions; α-helix mimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Cyclobutanes / chemistry
  • Cyclobutanes / pharmacology*
  • Humans
  • Protein Binding / drug effects
  • Protein Conformation, alpha-Helical / drug effects
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • 2-aminocyclobutanecarboxylic acid
  • CNBP protein, human
  • Carboxylic Acids
  • Cyclobutanes
  • RNA-Binding Proteins
  • Tumor Suppressor Protein p53