NEUVILLE, Maxime; BOURGEAIS, Mathieu; LI, Bo; VARAJAO, Laetitia; HALLÉ, François; GOUDREAU, Sébastien; THINON, Emmanuelle; PASCO, Morgane; KHATIB, Abdel-Majid; GUICHARD, Gilles

doi:10.1021/acs.jmedchem.4c01762

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NEUVILLE, Maxime

Institut de Chimie Organique et Analytique [ICOA]

BOURGEAIS, Mathieu

LI, Bo

South China University of Technology [Guangzhou] [SCUT]
Sichuan University [Chengdu] [SCU]

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Article de revue

Ce document a été publié dans

Journal of Medicinal Chemistry. 2024-12-25, vol. 68, n° 1, p. 236-246

Résumé en anglais

Combining helical foldamers with α-peptides canproduce α-helix mimetics with a reduced peptide character andenhanced resistance to proteolysis. Previously, we engineered ahybrid peptide-oligourea sequence replicating the N-terminal α-helical domain of p53 to achieve high affinity binding to hDM2.Here, we further advance this strategy by combining the foldamerapproach with side chain cross-linking to create more constrainedcell-permeable inhibitors capable of effectively engaging the targetwithin cells. Starting from the crystal structure of the foldamer-hDM2 complex, we identified specific sites suitable for stapling,and generated a small library of macrocyclic foldamer-peptidehybrids. The most promising binders were subsequently optimizedfor cellular uptake and tested in a cellular assay. We observed that the introduction of a short segment of positively charged residuesat the N-terminus of the sequence led to inhibitors that exhibited cytotoxic activity independently of p53. In contrast, neutralacetylated peptide-foldamer macrocycles demonstrated activity in a p53-dependent manner.< Réduire

URI

https://oskar-bordeaux.fr/handle/20.500.12278/206895

DOI

http://dx.doi.org/10.1021/acs.jmedchem.4c01762

Project ANR

Hélices chimériques aux propriétés innovantes pour l'inhibition des interactions protéine-protéine - ANR-15-CE07-0010

Unités de recherche

BRIC (Bordeaux of Institute of Oncology) - U1312