Nuclear Localization of Dengue Virus (DENV) 1-4 Non-Structural Protein 5; Protection Against All 4 DENV Serotypes by the Inhibitor Ivermectin

Antiviral Res. 2013 Sep;99(3):301-6. doi: 10.1016/j.antiviral.2013.06.002. Epub 2013 Jun 14.

Abstract

Infection by one of the 4 distinct serotypes of dengue virus (DENV) threatens >40% of the world's population, with no efficacious vaccine or antiviral agent currently available. DENV replication through the virus-encoded nonstructural protein (NS) 5 protein occurs in the infected cell cytoplasm, but NS5 from DENV2 has thus far been shown to localize strongly in the nucleus throughout infection. Here we use specific antibodies cross-reactive with NS5 from DENV1-4 to demonstrate nuclear localization of NS5 from all DENV serotypes for the first time in both infected as well as transfected cells, although to differing extents. The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/β in vitro, and protected against infection from DENV1-4. Ivermectin thus has potential in the clinical setting as a dengue antiviral.

Keywords: Dengue; Dengue virus; Flavivirus; Ivermectin; Nonstructural protein-5; Nuclear import.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cell Nucleus / virology*
  • Cytoplasm / virology
  • Dengue / drug therapy
  • Dengue / virology*
  • Dengue Virus / classification
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • Dengue Virus / metabolism
  • Humans
  • Ivermectin / pharmacology*
  • Protein Transport / drug effects
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*

Substances

  • Antiviral Agents
  • NS5 protein, dengue virus
  • Viral Nonstructural Proteins
  • Ivermectin