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

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 s...

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Published inCell 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
LanguageEnglish
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
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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.
AbstractList 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.
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.
Author 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 Kramer Cheng-Feng Qin Hongmin Li
AuthorAffiliation Wadsworth Center, New York State Department of Health, 120 New ScotlandAve, Albany, NY 12208, USA Department of Virology, State Key Laboratory ofPathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA Department of Food Science, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong 524000, China The Neural Stem Cell Institute, 1 Discovery Drive, Rensselaer, NY 12144, USA Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, TX 77555, USA Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Dalian University, Dalian, Liaoning 116622, China Center fbr Functional Genomics, University at Albany, Rensselaer, NY 12144, USA Department of Biomedical Sciences, School of Public Health, University at Albany, PO Box
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28685770$$D View this record in MEDLINE/PubMed
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Copyright Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 2017
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Copyright © 2017 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 2017 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
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DocumentTitleAlternate Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
Zika inhibitor
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Issue 8
Keywords protease
Zika virus
inhibitor
NS2B-NS3
Language English
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Notes 31-1568
Zika virus; inhibitor; protease; NS2B-NS3
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.
These three authors contributed equally to this work.
OpenAccessLink https://www.nature.com/articles/cr201788.pdf
PMID 28685770
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Snippet Recent outbreaks of Zika virus （ZIKV） highlight an urgent need for therapeutics. The protease complex NS2B- NS3 plays essential roles during flaviviral...
Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2B-NS3 plays essential roles during flaviviral...
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SubjectTerms 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
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Title Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
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