Multicomponent Peptide Stapling as a Diversity‐Driven Tool for the Development of Inhibitors of Protein–Protein Interactions. (6th February 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Angewandte Chemie. Volume 132:Number 13(2020)
• Page Start: 5273
• Page End: 5279
• Publication Date: 2020-02-06
• Subjects: Krebs -- HSQC-NMR -- p53-MDM2/X -- Geklammerte Peptide -- Ugi-Reaktion; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201916257
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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. Abstract : Eine effektive Strategie für die Entwicklung von α‐helikalen Peptiden durch Ugi‐Klammerung wird beschrieben. Die hochwirksame duale antagonistische Wirkung von MDM2‐ und MDMX‐bindendem p53 wird auf der Grundlage von drei bi‐orthogonalen Assays demonstriert, z. B. Fluoreszenz‐Polarisation, mikroskalige Thermophorese und 2D‐NMR. Zusätzlich wurden mehrere Cokristallstrukturen mit MDM2 erhalten.