Zika virus NS2B/NS3 proteinase: A new target for an old drug - Suramin a lead compound for NS2B/NS3 proteinase inhibition

Author(s)

Coronado, Monika Aparecida ^[1] ; Eberle, Raphael Josef ^[1] ; Bleffert, Nicole ^{[2, 3]} ; Feuerstein, Sophie ^{[2, 3]} ; Olivier, Danilo Silva ^[1] ; de Moraes, Fabio Rogerio ^[1] ; Willbold, Dieter ^{[2, 3]} ; Arni, Raghuvir Krishnaswamy ^[1]

Affiliation

^[1] Univ Estadual Paulista, UNESP, Dept Phys, Multiuser Ctr Biomol Innovat, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Forschungszentrum Julich, Inst Complex Syst Struct Biochem ICS 6, Julich - Germany

^[3] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, Univ Str, Dusseldorf - Germany

• Document type: Journal article
• Source: Antiviral Research; v. 160, p. 118-125, DEC 2018.
• Web of Science Citations: 6

Abstract

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 IC50 of 47 mu M. Using fluorescence spectroscopy results we could determine a k(d) value of 28 mu M 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. (AU)

• FAPESP's process: 09/53989-4 - Acquisition of a nuclear magnetic resonance spectrometer for studies of biomolecules
• Grantee: Raghuvir Krishnaswamy Arni
• Support type: Multi-user Equipment Program
• FAPESP's process: 16/08104-8 - Structural and functional aspects of two DNA binding proteins encoded by Corynebacterium pseudotuberculosis
• Grantee: Raphael Josef Eberle
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 16/12904-0 - Mechanism and Molecular Interactions of Bioactive molecules with NS3 protease from Zika virus.
• Grantee: Monika Aparecida Coronado
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/18868-2 - Multi-user equipment acquisition for molecular and structural biology
• Grantee: Raghuvir Krishnaswamy Arni
• Support type: Multi-user Equipment Program
• FAPESP's process: 15/13765-0 - Structural Studies and Characterization of Proteins by X-ray Crystallography and Nuclear Magnetic Resonance. Structural investigations and biophysics of molecular mechanisms of functional proteins.
• Grantee: Raghuvir Krishnaswamy Arni
• Support type: Regular Research Grants