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Cell-Permeable Peptide Inhibitors of the p53-hDM2 Interaction via Foldamer Helix Mimicry and Bis-Thioether Stapling

dc.rights.licenseopenen_US
hal.structure.identifierInstitut de Chimie Organique et Analytique [ICOA]
dc.contributor.authorNEUVILLE, Maxime
dc.contributor.authorBOURGEAIS, Mathieu
hal.structure.identifierSouth China University of Technology [Guangzhou] [SCUT]
hal.structure.identifierSichuan University [Chengdu] [SCU]
dc.contributor.authorLI, Bo
dc.contributor.authorVARAJAO, Laetitia
hal.structure.identifierAcides Nucléiques : Régulations Naturelle et Artificielle [ARNA]
dc.contributor.authorHALLÉ, François
hal.structure.identifierSans affiliation
dc.contributor.authorGOUDREAU, Sébastien
hal.structure.identifierLaboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University
dc.contributor.authorTHINON, Emmanuelle
hal.structure.identifierInstitut Européen de Chimie et Biologie [IECB]
dc.contributor.authorPASCO, Morgane
IDREF: 152520791
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorKHATIB, Abdel-Majid
hal.structure.identifierUniversité de Bordeaux [UB]
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
hal.structure.identifierInstitut Européen de Chimie et Biologie [IECB]
hal.structure.identifierInstitut Polytechnique de Bordeaux [Bordeaux INP]
dc.contributor.authorGUICHARD, Gilles
IDREF: 084339268
dc.date.accessioned2025-06-13T07:59:52Z
dc.date.available2025-06-13T07:59:52Z
dc.date.issued2024-12-25
dc.identifier.issn0022-2623en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/206895
dc.description.abstractEnCombining 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.
dc.description.sponsorshipHélices chimériques aux propriétés innovantes pour l'inhibition des interactions protéine-protéine - ANR-15-CE07-0010en_US
dc.language.isoENen_US
dc.title.enCell-Permeable Peptide Inhibitors of the p53-hDM2 Interaction via Foldamer Helix Mimicry and Bis-Thioether Stapling
dc.typeArticle de revueen_US
dc.identifier.doi10.1021/acs.jmedchem.4c01762en_US
dc.subject.halChimieen_US
bordeaux.journalJournal of Medicinal Chemistryen_US
bordeaux.page236-246en_US
bordeaux.volume68en_US
bordeaux.hal.laboratoriesBRIC (Bordeaux of Institute of Oncology) - U1312en_US
bordeaux.issue1en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierhal-04931235
hal.version1
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal%20of%20Medicinal%20Chemistry&rft.date=2024-12-25&rft.volume=68&rft.issue=1&rft.spage=236-246&rft.epage=236-246&rft.eissn=0022-2623&rft.issn=0022-2623&rft.au=NEUVILLE,%20Maxime&BOURGEAIS,%20Mathieu&LI,%20Bo&VARAJAO,%20Laetitia&HALL%C3%89,%20Fran%C3%A7ois&rft.genre=article


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