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Cell Res. 2017 Aug;27(8):1046-1064. doi: 10.1038/cr.2017.88. Epub 2017 Jul 7.

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction.

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Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY 12208, USA.
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Food Science, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong 524000, China.
The Neural Stem Cell Institute, 1 Discovery Drive, Rensselaer, NY 12144, USA.
Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Dalian University, Dalian, Liaoning 116622, China.
Center for Functional Genomics, University at Albany, Rensselaer, NY 12144, USA.
Department of Biomedical Sciences, School of Public Health, University at Albany, PO Box 509, Empire State Plaza, Albany, NY 12201, USA.
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China.


Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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