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

• Published in: Angewandte Chemie International Edition 2016-09, Vol.55 (37), p.11096-11100
• Main Authors: Grison, Claire M., Miles, Jennifer A., Robin, Sylvie, Wilson, Andrew J., Aitken, David J.
• Format: Article
• Language: English
• Subjects: Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Communication; Communications; Cyclobutanes - chemistry; Cyclobutanes - pharmacology; foldamers; Humans; inhibitors; peptidomimetics; Protein Binding - drug effects; Protein Conformation, alpha-Helical - drug effects; protein-protein interactions; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; α-helix mimetics
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201604517

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. Match and mimic: α/β/γ‐Peptides featuring trans‐2‐aminocyclobutanecarboxylic acid (tACBC) as the “structuring” β‐amino acid component adopt a 12,13‐helical conformation and can behave as selective inhibitors of the p53/hDM2 interaction.