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Multicomponent Peptide Stapling as a Diversity‐Driven Tool for the Development of Inhibitors of Protein–Protein Interactions
Author(s) -
Ricardo Manuel G.,
Ali Ameena M.,
Plewka Jacek,
Surmiak Ewa,
Labuzek Beata,
Neochoritis Constantinos G.,
Atmaj Jack,
Skalniak Lukasz,
Zhang Ran,
Holak Tad A.,
Groves Matthew,
Rivera Daniel G.,
Dömling Alexander
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201916257
Subject(s) - microscale thermophoresis , chemistry , peptide , small molecule , biophysics , combinatorial chemistry , protein–protein interaction , intein , stereochemistry , biochemistry , biology , gene , rna , rna splicing
Stapled peptides are chemical entities in‐between biologics and small molecules, which have proven to be the solution to high affinity protein–protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction‐based stapling is an effective strategy for the development of α‐helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53‐MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo ‐ and endo ‐cyclic hydrophobic moieties at the side chain cross‐linkers. The interaction of the Ugi‐staple fragments with the target protein was demonstrated by crystallography.