Ivermectin effectively inhibits hepatitis E virus replication, requiring the host nuclear transport protein importin α1

Abstract

We show that ivermectin, an FDA-approved anti-parasitic drug, effectively inhibits infection with hepatitis E virus (HEV) genotypes 1 and 3 in a range of cell culture models, including hepatic and extrahepatic cells. Long-term treatment showed no clear evidence of the development of drug resistance. Gene silencing of importin-α1, a cellular target of ivermectin and a key member of the host nuclear transport complex, inhibited viral replication and largely abolished the anti-HEV effect of ivermectin.

Mono- and combinational drug therapies for global viral pandemic preparedness

“…Recently, we have tested several experimental, investigational, and approved BSAs against different viruses. We identified novel activities for saliphenylhalamide, gemcitabine, obatoclax, SNS-032, flavopiridol, nelfinavir, salinomycin, amodiaquine, obatoclax, emetine, homoharringtonine, atovaquone and ciclesonide, dalbavancin, vemurafenib, MK-2206, ezetimibe, azacitidine, cyclosporine, minocycline, ritonavir, oritavancin, cidofovir, dibucaine, azithromycin, gefitinib, minocycline, pirlindole ivermectin, brequinar, homoharringtonine, azacytidine, itraconazole, lopinavir, nitazoxanide, umifenovir, sertraline, amodiaquine and aripiprazole ( Andersen et al., 2019 ; Bosl et al., 2019 ; Chen et al., 2020 ; Denisova et al., 2012 , 2014 ; Herring et al., 2021 ; Ianevski et al., 2018 , 2020c ; Kakkola et al., 2013 ; Ko et al., 2021 ; Kuivanen et al., 2017 ; Li et al., 2020 , 2021 ; Soderholm et al., 2016 ; Yang et al., 2021 ). These results suggest that the landscape of BSA activities is vast and that it can be further interrogated and expanded.…”

Chronic hepatitis E: Advancing research and patient care

“…102 By constructing reverse genetics systems, p6-based genotype 3 HEV models have been widely used in the field, and are capable of sustaining persistent replication or infection in various human cell lines. 77,103 Although reverse genetics systems are also available for genotype 4, 104 7 105 and rat HEV, 106 these models are either not sufficiently robust or have not been widely validated.…”

“…So far, several FDA-approved medications (e.g. azithromycin, 143 ivermectin, 103 niclosamide, 144 and gemcitabine 145 ) and an essential micronutrient (Zinc 146 ) have been shown to inhibit HEV in vitro (Table 2). We recommend that clinical testing of these agents should be preceded by extensive preclinical studies especially in relevant animal models that are already available.…”

“…A natural compound extracted from the plant species Aglaia foveolata; a potent and selective inhibitor of the eukaryotic initiation factor 4A Zinc 146 May inhibit HEV RdRp Cell lines An essential micronutrient Deptropine 155 involving the NF-jB-RIPK1-caspase axis Cell lines A classical histamine H1 receptor antagonist for treating asthmatic symptoms; but nowadays rarely used in the clinic Ivermectin 103 Involving the host nuclear transport protein importin a1…”

Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

“…Recently, we have tested several experimental, investigational, and approved BSAs against different viruses. We identified novel activities for saliphenylhalamide, gemcitabine, obatoclax, SNS-032, flavopiridole, nelfinavir, salinomycin, amodiaquine, obatoclax, emetine, homoharringtonine, atovaquone and ciclesonide, dalbavancin, vemurafenib, MK-2206, ezetimibe, azacitidine, cyclosporine, minocycline, ritonavir, oritavancin, cidofovir, dibucaine, azithromycin, gefitinib, minocycline, pirlindole ivermectin, brequinar, homoharringtonine, azacytidine, itraconazole, lopinavir, nitazoxanide, umifenovir, sertraline, amodiaquine and aripiprazole [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. These results suggest that the landscape of BSA activities is vast and that it can and should be further interrogated and expanded.…”