The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer

Antiviral Res. 2020 May;177:104760. doi: 10.1016/j.antiviral.2020.104760. Epub 2020 Mar 3.

Abstract

Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response. We previously identified the small molecule ivermectin as an inhibitor of HIV-1 integrase nuclear entry, subsequently showing ivermectin could inhibit DENV NS5 nuclear import, as well as limit infection by viruses such as HIV-1 and DENV. We show here that ivermectin's broad spectrum antiviral activity relates to its ability to target the host importin (IMP) α/β1 nuclear transport proteins responsible for nuclear entry of cargoes such as integrase and NS5. We establish for the first time that ivermectin can dissociate the preformed IMPα/β1 heterodimer, as well as prevent its formation, through binding to the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity. We show that ivermectin inhibits NS5-IMPα interaction in a cell context using quantitative bimolecular fluorescence complementation. Finally, we show for the first time that ivermectin can limit infection by the DENV-related West Nile virus at low (μM) concentrations. Since it is FDA approved for parasitic indications, ivermectin merits closer consideration as a broad spectrum antiviral of interest.

Keywords: Dengue virus; Flavivirus; Importins; Nuclear transport inhibitors; Viral infection; West nile virus; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects*
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Cricetinae
  • Flavivirus Infections / drug therapy
  • Ivermectin / pharmacology*
  • Kidney / cytology
  • Protein Binding
  • Vero Cells
  • alpha Karyopherins / antagonists & inhibitors*
  • alpha Karyopherins / metabolism
  • beta Karyopherins / antagonists & inhibitors*
  • beta Karyopherins / metabolism

Substances

  • alpha Karyopherins
  • beta Karyopherins
  • Ivermectin