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The Roles of LIM Kinase (LIMK) Inhibitors in the Regulation of Actin Dynamics During HIV-1 Infection

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dc.contributor.advisor Wu, YuntaoGuo, Jia Yi, Fei
dc.creator Yi, Fei 2016-09-28T10:23:03Z 2016-09-28T10:23:03Z 2016
dc.description.abstract A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during viral entry, the virus triggers early actin activity through hijacking chemokine coreceptor signaling which activates a viral dependency host factor cofilin and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIMK1 with siRNA inhibits HIV infection, no specific small molecule inhibitor of LIMK is available. Here we describe the design and discovery of novel classes of small molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK kinase activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses including EBOV, RVFV, VEEV, and HSV-1, suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum anti-viral drugs.
dc.format.extent 135 pages
dc.language.iso en
dc.rights Copyright 2016 Fei Yi
dc.subject Virology en_US
dc.subject Molecular biology en_US
dc.subject Microbiology en_US
dc.subject actin en_US
dc.subject antiviral drug en_US
dc.subject cofilin en_US
dc.subject HIV en_US
dc.subject kinase inhibitor en_US
dc.subject LIMK en_US
dc.title The Roles of LIM Kinase (LIMK) Inhibitors in the Regulation of Actin Dynamics During HIV-1 Infection
dc.type Dissertation Ph.D. Biosciences George Mason University

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