文献类型：期刊文献

英文题名：Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

作者：Li, Zhong[1];Brecher, Matthew[1];Deng, Yong-Qiang[2];Zhang, Jing[1];Sakamuru, Srilatha[3];Liu, Binbin[1,4];Huang, Ruili[3];Koetzner, Cheri A.[1];Allen, Christina A.[5];Jones, Susan A.[1];Chen, Haiying[6];Zhang, Na-Na[2];Tian, Min[2];Gao, Fengshan[1,7];Lin, Qishan[8];Banavali, Nilesh[1,9];Zhou, Jia[6];Boles, Nathan[5];Xia, Menghang[3];Kramer, Laura D.[1,9];Qin, Cheng-Feng[2,10];Li, Hongmin[1,9]

机构：[1]New York State Dept Hlth, Wadsworth Ctr, 120 New Scotland Ave, Albany, NY 12208 USA;[2]Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Dept Virol, Beijing 100071, Peoples R China;[3]NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA;[4]Guangdong Ocean Univ, Coll Food Sci & Technol, Dept Food Sci, Zhanjiang 524000, Guangdong, Peoples R China;[5]Neural Stem Cell Inst, 1 Discovery Dr, Rensselaer, NY 12144 USA;[6]Univ Texas Med Branch, Dept Pharmacol & Toxicol, Chem Biol Program, Galveston, TX 77555 USA;[7]Dalian Univ, Coll Life Sci & Technol, Dept Biochem & Mol Biol, Dalian 116622, Liaoning, Peoples R China;[8]SUNY Albany, Ctr Funct Genom, Rensselaer, NY 12144 USA;[9]SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, POB 509,Empire State Plaza, Albany, NY 12201 USA;[10]Guangzhou Med Univ, Guangzhou Peoples Hosp 8, Guangzhou 510060, Guangdong, Peoples R China

年份：2017

卷号：27

期号：8

起止页码：1046

外文期刊名：CELL RESEARCH

收录：SCI-EXPANDED(收录号：WOS:000406639800010)、、Scopus(收录号：2-s2.0-85026675178)、WOS

基金：We thank J Tang at the Wadsworth Center Tissue Culture Core facility for help in cell culture, E Eisele at the Biochemistry Core for assistance in CD experiments, and other core facilities at the Wadsworth Center, including the Applied Genomic Technologies Core for DNA sequencing, the Advanced Light Microscopy Core for immunofluorescence imaging, and the Tissue Culture Core for media. We also thank X Zhao at the University of Wisconsin-Madison for helpful discussion of neural progenitor cells. MB was partially supported by the NIH Biodefense and Emerging Infectious Disease training grant AI055429. CFQ was supported by the National Natural Science Foundation of China (NSFC) Excellent Young Scientist (81522025), Innovative Research Group (81621005), the National Key Research and Development Project of China (2016YFD0500304), the National Science and Technology Major Project of China (2017ZX09101005), and the Newton Advanced Fellowship from the UK Academy of Medical Sciences (NAF003\1003) and the NSFC (81661130162). BL was partially supported by a visiting scholarship sponsored by Guangdong Ocean University. FG was partially supported by a visiting scholarship sponsored by the China Scholarship Council. This work was partially supported by the Wadsworth Center flavivirus drug discovery seed funding (HL, NB, and LDK), by NIH grant DA038446 (JZ), and by the Intramural Research Program of NCATS, NIH (MX).

语种：英文

外文关键词：Zika virus; inhibitor; protease; NS2B-NS3

外文摘要：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.