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Tytuł:
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Zika virus NS2B/NS3 proteinase: A new target for an old drug - Suramin a lead compound for NS2B/NS3 proteinase inhibition.
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Autorzy:
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Coronado MA; Multiuser Center for Biomolecular Innovation, Department of Physics, Universidade Estadual Paulista (UNESP), São José do Rio Preto SP, 15054-000, Brazil. Electronic address: .
Eberle RJ; Multiuser Center for Biomolecular Innovation, Department of Physics, Universidade Estadual Paulista (UNESP), São José do Rio Preto SP, 15054-000, Brazil.
Bleffert N; Institute of Complex System, Structural Biochemistry (ICS-6), Forchungszentrum Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße, Germany.
Feuerstein S; Institute of Complex System, Structural Biochemistry (ICS-6), Forchungszentrum Jülich, Germany; Institute of Complex System, Structural Biochemistry (ICS-6), Forchungszentrum Jülich, Germany.
Olivier DS; Multiuser Center for Biomolecular Innovation, Department of Physics, Universidade Estadual Paulista (UNESP), São José do Rio Preto SP, 15054-000, Brazil.
de Moraes FR; Multiuser Center for Biomolecular Innovation, Department of Physics, Universidade Estadual Paulista (UNESP), São José do Rio Preto SP, 15054-000, Brazil.
Willbold D; Institute of Complex System, Structural Biochemistry (ICS-6), Forchungszentrum Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße, Germany.
Arni RK; Multiuser Center for Biomolecular Innovation, Department of Physics, Universidade Estadual Paulista (UNESP), São José do Rio Preto SP, 15054-000, Brazil. Electronic address: .
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Źródło:
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Antiviral research [Antiviral Res] 2018 Dec; Vol. 160, pp. 118-125. Date of Electronic Publication: 2018 Oct 28.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Amsterdam : Elsevier
Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981-
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MeSH Terms:
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Antiviral Agents/*pharmacology
Protease Inhibitors/*pharmacology
Suramin/*pharmacology
Viral Nonstructural Proteins/*antagonists & inhibitors
Zika Virus/*drug effects
Zika Virus/*enzymology
Antiparasitic Agents/chemistry ; Antiparasitic Agents/pharmacology ; Antiviral Agents/chemistry ; Drug Repositioning ; Inhibitory Concentration 50 ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Protease Inhibitors/chemistry ; Protein Binding ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/chemistry ; RNA Helicases/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/metabolism ; Suramin/chemistry ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
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Contributed Indexing:
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Keywords: Inhibitor; Lead compound; NS2B/NS3 proteinase; Suramin; Zika virus
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Substance Nomenclature:
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0 (Antiparasitic Agents)
0 (Antiviral Agents)
0 (NS2B protein, flavivirus)
0 (NS3 protein, flavivirus)
0 (Protease Inhibitors)
0 (Viral Nonstructural Proteins)
6032D45BEM (Suramin)
EC 3.4.21.- (Serine Endopeptidases)
EC 3.6.4.13 (RNA Helicases)
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Entry Date(s):
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Date Created: 20181106 Date Completed: 20190930 Latest Revision: 20190930
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Update Code:
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20240104
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DOI:
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10.1016/j.antiviral.2018.10.019
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PMID:
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30393012
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Zika virus infection is the focus of much research due to the medical and social repercussions. Due the role of the viral NS2B/NS3 proteinase in maturation of the viral proteins, it had become an attractive antiviral target. Numerous investigations on viral epidemiology, structure and function analysis, vaccines, and therapeutic drugs have been conducted around the world. At present, no approved vaccine or even drugs have been reported. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified the polyanion suramin, an approved antiparasitic drug with antiviral properties, as a potential inhibitor of Zika virus complex NS2B/NS3 proteinase with IC 50 of 47 μM. Using fluorescence spectroscopy results we could determine a k d value of 28 μM and had shown that the ligand does not affect the thermal stability of the protein. STD NMR spectroscopy experiments and molecular docking followed by molecular dynamics simulation identified the binding epitopes of the molecule and shows the mode of interaction, respectively. The computational analysis showed that suramin block the Ser135 residue and interact with the catalytically histidine residue.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
