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

• Published in: Cell research Vol. 27; no. 8; pp. 1046 - 1064
• Main Authors: Li, Zhong, Brecher, Matthew, Deng, Yong-Qiang, Zhang, Jing, Sakamuru, Srilatha, Liu, Binbin, Huang, Ruili, Koetzner, Cheri A, Allen, Christina A, Jones, Susan A, Chen, Haiying, Zhang, Na-Na, Tian, Min, Gao, Fengshan, Lin, Qishan, Banavali, Nilesh, Zhou, Jia, Boles, Nathan, Xia, Menghang, Kramer, Laura D, Qin, Cheng-Feng, Li, Hongmin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2017; Nature Publishing Group
• Subjects: 631/45/607/468; 631/80/86; 692/699/255/2514; 692/700/565/1436/2185; Animal models; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biomedical and Life Sciences; Cell Biology; Cell Line; Cells (biology); Docking; Drug development; Drugs; Female; High-throughput screening; Humans; Inhibitors; Life Sciences; Molecular Docking Simulation; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - virology; Niclosamide; Original; original-article; Outbreaks; Placenta; Placenta - metabolism; Placenta - virology; Pregnancy; RNA Helicases - chemistry; RNA Helicases - genetics; RNA Helicases - metabolism; Screening; Serine Endopeptidases - chemistry; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Vector-borne diseases; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Viremia; Virus Replication - drug effects; Virus Replication - physiology; Viruses; Zika virus; Zika Virus - chemistry; Zika Virus - physiology; Zika Virus Infection - drug therapy; Zika Virus Infection - genetics; Zika Virus Infection - metabolism; protease; Zika virus; inhibitor; NS2B-NS3
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2017.88

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.