Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection

Antimicrob Agents Chemother. 2020 Feb 21;64(3):e02373-19. doi: 10.1128/AAC.02373-19. Print 2020 Feb 21.

Abstract

The mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide that is associated with high morbidity and mortality. Currently, there are no effective drugs approved for the treatment of JEV infection. Drug-repurposing screening is an alternative approach to discover potential antiviral agents. In this study, high-content screening (HCS) of a natural extracts library was performed, and two hit FDA-approved Na+/K+-ATPase inhibitors, ouabain and digoxin, were identified as having robust efficiency against JEV infection with the selectivity indexes over 1,000. The results indicated that ouabain and digoxin blocked the JEV infection at the replication stage by targeting the Na+/K+-ATPase. Furthermore, it was proven that ouabain significantly reduced the morbidity and mortality caused by JEV in a BALB/c mouse model. This work demonstrated that Na+/K+-ATPase could serve as the target of treatment of JEV infection, and ouabain has the potential to be developed as an effective anti-JEV drug.

Keywords: Japanese encephalitis virus (JEV); Na+/K+-ATPase; digoxin; high-content screening (HCS); ouabain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Digoxin / therapeutic use
  • Encephalitis Virus, Japanese / pathogenicity*
  • Encephalitis, Japanese / drug therapy*
  • Encephalitis, Japanese / virology*
  • Enzyme Inhibitors / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Ouabain / therapeutic use
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • Enzyme Inhibitors
  • Ouabain
  • Digoxin
  • Sodium-Potassium-Exchanging ATPase