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dc.creatorKoneru, PC
dc.creatorFrancis, AC
dc.creatorDeng, N
dc.creatorRebensburg, SV
dc.creatorHoyte, AC
dc.creatorLindenberger, J
dc.creatorAdu-Ampratwum, D
dc.creatorLarue, RC
dc.creatorWempe, MF
dc.creatorEngelman, AN
dc.creatorLyumkis, D
dc.creatorFuchs, JR
dc.creatorLevy, RM
dc.creatorMelikyan, GB
dc.creatorKvaratskhelia, M
dc.date.accessioned2020-12-11T16:42:13Z
dc.date.available2020-12-11T16:42:13Z
dc.date.issued2019-05-01
dc.identifier.issn2050-084X
dc.identifier.issn2050-084X
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/4315
dc.identifier.other31120420 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/4333
dc.description.abstract© Koneru et al. Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10 fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.
dc.format.extente46344-
dc.language.isoen
dc.relation.hasparteLife
dc.relation.isreferencedbyeLife Sciences Publications, Ltd
dc.rightsCC BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHIV-1
dc.subjectallosteric inhibitors
dc.subjectinfectious disease
dc.subjectintegrase
dc.subjectmicrobiology
dc.subjectvirus
dc.subjectAllosteric Regulation
dc.subjectAntiviral Agents
dc.subjectHEK293 Cells
dc.subjectHIV Integrase
dc.subjectHIV Integrase Inhibitors
dc.subjectHeLa Cells
dc.subjectHumans
dc.subjectModels, Molecular
dc.subjectProtein Domains
dc.subjectProtein Multimerization
dc.subjectPyridines
dc.subjectStereoisomerism
dc.titleHiv-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.7554/eLife.46344
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.date.updated2020-12-11T16:42:09Z
refterms.dateFOA2020-12-11T16:42:13Z


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