Structure-based design of potent linear peptide inhibitors of the YAP-TEAD protein-protein interaction derived from the YAP omega-loop sequence

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2316-2319. doi: 10.1016/j.bmcl.2019.06.022. Epub 2019 Jun 18.

Abstract

The YAP-TEAD protein-protein interaction is a potential therapeutic target to treat cancers in which the Hippo signaling pathway is deregulated. However, the extremely large surface of interaction between the two proteins presents a formidable challenge for a small molecule interaction disrupter approach. We have accomplished progress towards showing the feasibility of this approach by the identification of a 15-mer peptide able to potently (nanomolar range) disrupt the YAP-TEAD interaction by targeting only one of the two important sites of interaction. This peptide, incorporating non-natural amino acids selected by structure-based design, is derived from the Ω-loop sequence 85-99 of YAP.

Keywords: Anticancer drug target; Protein-protein interaction (PPI) inhibitors; Structure-based design.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / chemistry
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Structure
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Binding / drug effects
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Peptides
  • Small Molecule Libraries
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human