Journal of virology 2017 04 05() pii 10.1128/JVI.02418-16
A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity through hijacking chemokine coreceptor signaling which activates a host dependency factor cofilin and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIMK1 with shRNA inhibits HIV infection, no specific small molecule inhibitor of LIMK was 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.IMPORTANCE The actin cytoskeleton is a structure that gives the cell shape and ability to migrate. Viruses frequently rely on actin dynamics for entry and intracellular migration. In cells, actin dynamics are regulated by kinases such as the LIM domain kinase (LIMK) that regulates actin activity through phosphorylation of cofilin, an actin depolymerizing factor. Recent studies have found that LIMK/cofilin are targeted by viruses such as HIV-1 for propelling viral intracellular migration. Although inhibiting LIMK1 expression blocks HIV-1 infection, no highly specific LIMK inhibitor is available. This study describes the design, medicinal synthesis, and discovery of small molecule LIMK inhibitors for blocking HIV-1 and several other viruses. This study emphasizes the feasibility of developing LIMK inhibitors as broad-spectrum antiviral drugs.