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

Sundy N.Y. Yang, Sarah C. Atkinson, Chunxiao Wang, Alexander Lee, Marie Ann Bogoyevitch, Natalie A. Borg, David A. Jans

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Article number104760
Number of pages9
JournalAntiviral Research
Volume177
DOIs
Publication statusPublished - May 2020

Keywords

  • flavivirus
  • nuclear transport inhibitors
  • importins
  • viral infection
  • West Nile Virus
  • dengue virus
  • Zika virus

Cite this