Premium
Structure‐Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1
Author(s) -
McGrath Sally,
Tortorici Marcello,
Drouin Ludovic,
Solanki Savade,
Vidler Lewis,
Westwood Isaac,
Gimeson Peter,
Van Montfort Rob,
Hoelder Swen
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201700747
Subject(s) - isothermal titration calorimetry , peptide , repressor , chemistry , linker , small molecule , lac repressor , biochemistry , computational biology , transcription factor , microbiology and biotechnology , biology , gene , computer science , operating system
Abstract TLE1 is an oncogenic transcriptional co‐repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein–protein interaction represents a putative cancer target, but no small‐molecule inhibitors have been published for this challenging interface. Herein, the structure‐enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four‐carbon‐atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof‐of‐concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five‐fold higher K d than that of the unconstrained peptide. The co‐crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well‐conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors.