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.
Description
The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer - ScienceDirect
%0 Journal Article
%1 yang2020broad
%A Yang, Sundy N.Y.
%A Atkinson, Sarah C.
%A Wang, Chunxiao
%A Lee, Alexander
%A Bogoyevitch, Marie A.
%A Borg, Natalie A.
%A Jans, David A.
%D 2020
%J Antiviral Research
%K covid-19 ivermectin
%P 104760
%R https://doi.org/10.1016/j.antiviral.2020.104760
%T The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer
%U http://www.sciencedirect.com/science/article/pii/S0166354219307211
%V 177
%X 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.
@article{yang2020broad,
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.},
added-at = {2020-07-23T19:03:01.000+0200},
author = {Yang, Sundy N.Y. and Atkinson, Sarah C. and Wang, Chunxiao and Lee, Alexander and Bogoyevitch, Marie A. and Borg, Natalie A. and Jans, David A.},
biburl = {https://www.bibsonomy.org/bibtex/2ff6c9f9ed187a950aeea99b848bc7831/fordham1},
description = {The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer - ScienceDirect},
doi = {https://doi.org/10.1016/j.antiviral.2020.104760},
interhash = {6ec925fed38b85e8a521b468969928d4},
intrahash = {ff6c9f9ed187a950aeea99b848bc7831},
issn = {0166-3542},
journal = {Antiviral Research},
keywords = {covid-19 ivermectin},
pages = 104760,
timestamp = {2022-10-05T15:26:52.000+0200},
title = {The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer},
url = {http://www.sciencedirect.com/science/article/pii/S0166354219307211},
volume = 177,
year = 2020
}