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dc.contributor.authorPatel, Disha
dc.contributor.authorAntwi, Janet
dc.contributor.authorKoneru, Pratibha
dc.contributor.authorSerrao, Erik
dc.contributor.authorForli, Stefano
dc.contributor.authorKessl, Jacques
dc.contributor.authorFeng, Lei
dc.contributor.authorDeng, Nanjie
dc.contributor.authorLevy, Ronald
dc.contributor.authorFuchs, James
dc.contributor.authorOlson, Arthur
dc.contributor.authorEngelman, Alan
dc.contributor.authorBauman, Joseph
dc.contributor.authorKvaratskhelia, Mamuka
dc.contributor.authorArnold, Eddy
dc.date.accessioned2019-10-05T03:27:17Z
dc.date.issued2016
dc.identifier.citationPatel, Disha, Janet Antwi, Pratibha C. Koneru, Erik Serrao, Stefano Forli, Jacques J. Kessl, Lei Feng, et al. 2016. “A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.” Journal of Biological Chemistry 291 (45): 23569–77. https://doi.org/10.1074/jbc.m116.753384.
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41482919*
dc.description.abstractHIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 m and impaired HIV-1 infection of T cells at an EC50 of 36 m. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structure-based development of second-generation ALLINIs.
dc.language.isoen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology
dash.licenseLAA
dc.titleA New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalThe Journal of Biological Chemistry
dash.depositing.authorEngelman, Alan N.::d24f388fc75569a343fc8e6e8fe32650::600
dc.date.available2019-10-05T03:27:17Z
dash.workflow.comments1Science Serial ID 108884
dc.identifier.doi10.1074/jbc.M116.753384
dash.source.volume291;45
dash.source.page23569


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