期刊
CELL RESEARCH
卷 27, 期 8, 页码 1046-1064出版社
SPRINGERNATURE
DOI: 10.1038/cr.2017.88
关键词
Zika virus; inhibitor; protease; NS2B-NS3
类别
资金
- NIH Biodefense and Emerging Infectious Disease [AI055429]
- National Natural Science Foundation of China (NSFC) Excellent Young Scientist [81522025]
- Innovative Research Group [81621005]
- National Key Research and Development Project of China [2016YFD0500304]
- National Science and Technology Major Project of China [2017ZX09101005]
- Newton Advanced Fellowship from the UK Academy of Medical Sciences [NAF003\1003]
- NSFC [81661130162]
- Guangdong Ocean University
- China Scholarship Council
- Wadsworth Center
- NIH [DA038446]
- Intramural Research Program of NCATS, NIH
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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