Abstract：
: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.
journal_name
Cell Resjournal_title
Cell researchauthors
Li Z,Brecher M,Deng YQ,Zhang J,Sakamuru S,Liu B,Huang R,Koetzner CA,Allen CA,Jones SA,Chen H,Zhang NN,Tian M,Gao F,Lin Q,Banavali N,Zhou J,Boles N,Xia M,Kramer LD,Qin CF,Li Hdoi
10.1038/cr.2017.88subject
Has Abstractpub_date
2017-08-01 00:00:00pages
1046-1064issue
8eissn
1001-0602issn
1748-7838pii
cr201788journal_volume
27pub_type
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