Polysulfonate suramin inhibits Zika virus infection

Antiviral Res. 2017 Jul;143:186-194. doi: 10.1016/j.antiviral.2017.04.017. Epub 2017 Apr 27.

Abstract

Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log10 PFU viral reduction with IC50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor.

Keywords: Antiviral; Heparan sulfate; Heparin; Suramin; Zika virus.

MeSH terms

  • Animals
  • Antibodies, Viral
  • Chlorates / pharmacology
  • Chlorocebus aethiops
  • DNA Helicases / metabolism
  • Dextran Sulfate / antagonists & inhibitors
  • Flavivirus / drug effects
  • Glycosaminoglycans / pharmacology
  • Heparin / analogs & derivatives
  • Heparin / chemistry
  • Heparin / pharmacology
  • Heparitin Sulfate / pharmacology
  • Inhibitory Concentration 50
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • RNA Helicases / chemistry
  • RNA Helicases / drug effects
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / drug effects
  • Suramin / administration & dosage
  • Suramin / antagonists & inhibitors*
  • Vero Cells
  • Viral Envelope Proteins / metabolism
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / drug effects
  • Virus Internalization / drug effects
  • Virus Replication / drug effects
  • Zika Virus / drug effects*
  • Zika Virus / physiology
  • Zika Virus Infection / prevention & control*
  • Zika Virus Infection / virology

Substances

  • Antibodies, Viral
  • Chlorates
  • Glycosaminoglycans
  • NS3 protein, flavivirus
  • Viral Envelope Proteins
  • Viral Nonstructural Proteins
  • Suramin
  • Heparin
  • Dextran Sulfate
  • Heparitin Sulfate
  • Serine Endopeptidases
  • DNA Helicases
  • RNA Helicases
  • sodium chlorate