Inhibition of α-helix-mediated protein-protein interactions using designed molecules

Valeria Azzarito*, Kérya Long, Natasha S. Murphy, Andrew J. Wilson

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

556 Citations (Scopus)

Abstract

Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads-and how criteria applied to these may differ from conventional small-molecule drugs-are summarized.

Original languageEnglish
Pages (from-to)161-173
Number of pages13
JournalNature Chemistry
Volume5
Issue number3
DOIs
Publication statusPublished - Mar 2013

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering

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