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

Infection by RNA viruses such as human immunodeficiency virus-1, influenza, and dengue virus 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 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 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 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 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.

https://pubmed.ncbi.nlm.nih.gov/32135219/