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

Zhong Li, Matthew Brecher, Yong Qiang Deng, Jing Zhang, Srilatha Sakamuru, Binbin Liu, Ruili Huang, Cheri A. Koetzner, Christina A. Allen, Susan A. Jones, Haiying Chen, Na Na Zhang, Min Tian, Fengshan Gao, Qishan Lin, Nilesh Banavali, Jia Zhou, Nathan Boles, Menghang Xia, Laura D. KramerCheng Feng Qin, Hongmin Li

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2BNS3 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 NS2BNS3 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.

Original languageEnglish (US)
Pages (from-to)1046-1064
Number of pages19
JournalCell Research
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2017

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Keywords

  • Inhibitor
  • NS2B-NS3
  • Protease
  • Zika virus

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, Z., Brecher, M., Deng, Y. Q., Zhang, J., Sakamuru, S., Liu, B., Huang, R., Koetzner, C. A., Allen, C. A., Jones, S. A., Chen, H., Zhang, N. N., Tian, M., Gao, F., Lin, Q., Banavali, N., Zhou, J., Boles, N., Xia, M., ... Li, H. (2017). Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Research, 27(8), 1046-1064. https://doi.org/10.1038/cr.2017.88