Volume 27, No 8, Aug 2017
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 27 Issue 8, August 2017: 1046-1064
ORIGINAL ARTICLES
Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
Zhong Li1,*, Matthew Brecher1,*, Yong-Qiang Deng2,*, Jing Zhang1, Srilatha Sakamuru3, Binbin Liu1,4, Ruili Huang3, Cheri A Koetzner1, Christina A Allen5, Susan A Jones1, Haiying Chen6, Na-Na Zhang2, Min Tian2, Fengshan Gao1,7, Qishan Lin8, Nilesh Banavali1,9, Jia Zhou6, Nathan Boles5, Menghang Xia3, Laura D Kramer1,9, Cheng-Feng Qin2,10 and Hongmin Li1,9
1Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY 12208, USA;
2Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
3National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA;
4Department of Food Science, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong 524000, China;
5The Neural Stem Cell Institute, 1 Discovery Drive, Rensselaer, NY 12144, USA;
6Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, TX 77555, USA;
7Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Dalian University, Dalian, Liaoning 116622, China;
8Center for Functional Genomics, University at Albany, Rensselaer, NY 12144, USA;
9Department of Biomedical Sciences, School of Public Health, University at Albany, PO Box 509, Empire State Plaza, Albany, NY 12201, USA;
10Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China
Correspondence: Cheng-Feng Qin, Tel: +86-10-66948604 E-mail: qincf@bmi.ac.cn; Hongmin Li, Tel: +1 518 4734201(Hongmin.li@health.ny.gov)
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.
10.1038/cr.2017.88
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