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Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48
Author(s) -
Hart Peter 't,
Hommen Pascal,
Noisier Anaïs,
Krzyzanowski Adrian,
Schüler Darijan,
Porfetye Arthur T.,
Akbarzadeh Mohammad,
Vetter Ingrid R.,
Adihou Hélène,
Waldmann Herbert
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202009749
Subject(s) - peptide , chemistry , rational design , combinatorial chemistry , biochemistry , stereochemistry , nanotechnology , materials science
The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein–protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1‐derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K D value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono‐ and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure‐based design is a suitable strategy for inhibitor development targeting PPIs.