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dc.rights.licenseopenen_US
hal.structure.identifierUniversité de Bordeaux [UB]
dc.contributor.authorAKNIN, Cindy
dc.contributor.authorSMITH, Elena
dc.contributor.authorMARCHAND, Christophe
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorANDRÉOLA, Marie-Line
dc.contributor.authorPOMMIER, Yves
dc.contributor.authorMÉTIFIOT, Mathieu
dc.date.accessioned2023-06-12T15:14:01Z
dc.date.available2023-06-12T15:14:01Z
dc.date.issued2019-10
dc.identifier.issn1420-3049en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/182653
dc.description.abstractEnCurrently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C-terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure-activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enHIV-1
dc.subject.enINSTI resistance
dc.subject.enDNA-binding inhibitor
dc.subject.enhigh-throughput screening
dc.subject.endrug discovery
dc.title.enDiscovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening
dc.typeArticle de revueen_US
dc.identifier.doi10.3390/molecules24203675en_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologie/Virologieen_US
bordeaux.journalMoleculesen_US
bordeaux.page3675en_US
bordeaux.volume24en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.issue20en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierhal-02340294
hal.version1
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=Molecules&rft.date=2019-10&rft.volume=24&rft.issue=20&rft.spage=3675&rft.epage=3675&rft.eissn=1420-3049&rft.issn=1420-3049&rft.au=AKNIN,%20Cindy&SMITH,%20Elena&MARCHAND,%20Christophe&ANDR%C3%89OLA,%20Marie-Line&POMMIER,%20Yves&rft.genre=article


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