Selectivity for strand-transfer over 3'-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme-DNA interactions in the active site.
| dc.rights.license | open | en_US |
| hal.structure.identifier | Microbiologie Fondamentale et Pathogénicité [MFP] | |
| dc.contributor.author | METIFIOT, Mathieu | |
| dc.contributor.author | JOHNSON, Barry C | |
| hal.structure.identifier | Microbiologie Fondamentale et Pathogénicité [MFP] | |
| dc.contributor.author | KISELEV, Evgeny | |
| dc.contributor.author | ZHAO, Xue Zhi | |
| dc.contributor.author | BURKE, Terrence R | |
| hal.structure.identifier | Matériaux fonctionnels et photonique [MFP] | |
| dc.contributor.author | MARCHAND, Christophe | |
| dc.contributor.author | HUGHES, Stephen H | |
| hal.structure.identifier | Microbiologie Fondamentale et Pathogénicité [MFP] | |
| dc.contributor.author | POMMIER, Yves | |
| dc.date.accessioned | 2023-11-08T12:28:19Z | |
| dc.date.available | 2023-11-08T12:28:19Z | |
| dc.date.issued | 2016-08-19 | |
| dc.identifier.issn | 1362-4962 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/184681 | |
| dc.description.abstractEn | Integrase strand transfer inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA +1 and -1 bases, which flank the 3'-processing site, play a critical role for 3'-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3'-processing activity, becomes more active and more resistant to inhibition of 3'-processing by RAL and DTG in the absence of the -1 and +1 bases. Molecular modeling of HIV-1 integrase, together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3'-processing and ST reactions. The potency of integrase inhibitors against 3'-processing and their ability to overcome resistance is discussed. | |
| dc.language.iso | EN | en_US |
| dc.subject.en | Biocatalysis | |
| dc.subject.en | Catalytic Domain | |
| dc.subject.en | DNA | |
| dc.subject.en | Viral | |
| dc.subject.en | Drug Resistance | |
| dc.subject.en | Viral | |
| dc.subject.en | Guanine | |
| dc.subject.en | HIV Integrase | |
| dc.subject.en | HIV Integrase Inhibitors | |
| dc.subject.en | Ions | |
| dc.subject.en | Magnesium | |
| dc.subject.en | Models | |
| dc.subject.en | Molecular | |
| dc.subject.en | Mutation | |
| dc.subject.en | Substrate Specificity | |
| dc.title.en | Selectivity for strand-transfer over 3'-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme-DNA interactions in the active site. | |
| dc.title.alternative | Nucleic Acids Res | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1093/nar/gkw592 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Microbiologie et Parasitologie | en_US |
| dc.identifier.pubmed | 27369381 | en_US |
| bordeaux.journal | Nucleic Acids Research | en_US |
| bordeaux.page | 6896-906 | en_US |
| bordeaux.volume | 44 | en_US |
| bordeaux.hal.laboratories | MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234 | en_US |
| bordeaux.issue | 14 | en_US |
| bordeaux.institution | CNRS | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.import.source | pubmed | |
| hal.identifier | hal-04275206 | |
| hal.version | 1 | |
| hal.date.transferred | 2023-11-08T12:28:21Z | |
| hal.popular | non | en_US |
| hal.audience | Internationale | en_US |
| hal.export | true | |
| workflow.import.source | pubmed | |
| dc.rights.cc | Pas de Licence CC | en_US |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nucleic%20Acids%20Research&rft.date=2016-08-19&rft.volume=44&rft.issue=14&rft.spage=6896-906&rft.epage=6896-906&rft.eissn=1362-4962&rft.issn=1362-4962&rft.au=METIFIOT,%20Mathieu&JOHNSON,%20Barry%20C&KISELEV,%20Evgeny&ZHAO,%20Xue%20Zhi&BURKE,%20Terrence%20R&rft.genre=article |
