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

Authors :: Furet P
Salem B
Mesrouze Y
Schmelzle T
Lewis I
Kallen J
Chène P
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Aug 15; Vol. 29 (16), pp. 2316-2319. Date of Electronic Publication: 2019 Jun 18.
Publication Year :: 2019
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.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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

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