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Modulation of the functional interfaces between retroviral intasomes and the human nucleosome.

dc.rights.licenseopenen_US
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorMAURO, Eric
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorLAPAILLERIE, Delphine
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorTUMIOTTO, Camille
hal.structure.identifierUnité en Sciences Biologiques et Biotechnologies de Nantes [US2B]
dc.contributor.authorCHARLIER, Cathy
hal.structure.identifierFaculdade de Medicina da Universidade do Porto [FMUP]
dc.contributor.authorMARTINS, F
dc.contributor.authorSOUSA, S F
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorMETIFIOT, Mathieu
dc.contributor.authorWEIGEL, P
hal.structure.identifierTokyo University of Science [Tokyo]
dc.contributor.authorYAMATSUGU, K
hal.structure.identifierTokyo University of Science [Tokyo]
dc.contributor.authorKANAI, M.
hal.structure.identifierInstitut Pasteur [Paris] [IP]
dc.contributor.authorMUNIER-LEHMANN, H
dc.contributor.authorRICHETTA, C
dc.contributor.authorMAISCH, M
dc.contributor.authorDUTRIEUX, J
dc.contributor.authorBATISSE, J
dc.contributor.authorRUFF, M
dc.contributor.authorDELELIS, O
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorLESBATS, P.
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorPARISSI, Vincent
dc.date.accessioned2024-07-16T13:15:12Z
dc.date.available2024-07-16T13:15:12Z
dc.date.issued2023-08-31
dc.identifier.issn2150-7511en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/200970
dc.description.abstractEnInfection by retroviruses as HIV-1 requires the stable integration of their genome into the host cells. This process needs the formation of integrase (IN)-viral DNA complexes, called intasomes, and their interaction with the target DNA wrapped around nucleosomes within cell chromatin. To provide new tools to analyze this association and select drugs, we applied the AlphaLISA technology to the complex formed between the prototype foamy virus (PFV) intasome and nucleosome reconstituted on 601 Widom sequence. This system allowed us to monitor the association between both partners and select small molecules that could modulate the intasome/nucleosome association. Using this approach, drugs acting either on the DNA topology within the nucleosome or on the IN/histone tail interactions have been selected. Within these compounds, doxorubicin and histone binders calixarenes were characterized using biochemical, molecular simulations and cellular approaches. These drugs were shown to inhibit both PFV and HIV-1 integration . Treatment of HIV-1-infected PBMCs with the selected molecules induces a decrease in viral infectivity and blocks the integration process. Thus, in addition to providing new information about intasome-nucleosome interaction determinants, our work also paves the way for further unedited antiviral strategies that target the final step of intasome/chromatin anchoring. IMPORTANCE In this work, we report the first monitoring of retroviral intasome/nucleosome interaction by AlphaLISA. This is the first description of the AlphaLISA application for large nucleoprotein complexes (>200 kDa) proving that this technology is suitable for molecular characterization and bimolecular inhibitor screening assays using such large complexes. Using this system, we have identified new drugs disrupting or preventing the intasome/nucleosome complex and inhibiting HIV-1 integration both and in infected cells. This first monitoring of the retroviral/intasome complex should allow the development of multiple applications including the analyses of the influence of cellular partners, the study of additional retroviral intasomes, and the determination of specific interfaces. Our work also provides the technical bases for the screening of larger libraries of drugs targeting specifically these functional nucleoprotein complexes, or additional nucleosome-partner complexes, as well as for their characterization.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enHumans
dc.subject.enNucleosomes
dc.subject.enHistones
dc.subject.enVirus Integration
dc.subject.enChromatin
dc.subject.enRetroviridae
dc.subject.enIntegrases
dc.subject.enDNA
dc.subject.enViral
dc.subject.enSpumavirus
dc.title.enModulation of the functional interfaces between retroviral intasomes and the human nucleosome.
dc.title.alternativemBioen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1128/mbio.01083-23en_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologieen_US
dc.identifier.pubmed37382440en_US
bordeaux.journalmBioen_US
bordeaux.pagee0108323en_US
bordeaux.volume14en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.issue4en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=mBio&rft.date=2023-08-31&rft.volume=14&rft.issue=4&rft.spage=e0108323&rft.epage=e0108323&rft.eissn=2150-7511&rft.issn=2150-7511&rft.au=MAURO,%20Eric&LAPAILLERIE,%20Delphine&TUMIOTTO,%20Camille&CHARLIER,%20Cathy&MARTINS,%20F&rft.genre=article


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