Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Abstract

Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV. IMPORTANCE Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases. FIG 2 Comparative effects of arbidol on infection by MLV pseudoviruses bearing LASV or other viral glycoproteins: LASV, LCMV, and Junin GP (A) and LASV GP and influenza virus HA (B). MLV pseudoviruses bearing LASV GP, LCMV GP, Junin GP, or WSN influenza HA and NA were prepared as described in Materials and Methods. BSC-1 cells were pretreated with the indicated concentrations of arbidol and then processed an...

Potential antiviral options against SARS-CoV-2 infection

“…It also showed broad-spectrum antiviral activity. It inhibited ZIKV, DENV, HCV, MERS-CoV, SARS-CoV, SARS-CoV-2, RRV, SINV, WNV, YFV, EBOV, LASV, RABV, VSV and HSV-1 viruses (https://doi.org/10.1101/2020.03.25.008482) (Boonyasuppayakorn et al, 2014;Dyall et al, 2014;Hulseberg et al, 2019;Mazzon et al, 2019;Sakurai et al, 2018;Zhou et al, 2017). It could be pursued as a potential anti-SARS-CoV-2 drug candidate.…”

Discovery and development of safe-in-man broad-spectrum antiviral agents

“…Enoxacin is an oral broad-spectrum fluoroquinolone antibiotic, which also possesses anti-HCV and anti-HIV-1 activities in immortalized cell cultures (Kashiwase et al, 1999;Young et al, 2010). Amodiaquine is an anti-malaria drug, which also possesses antiviral activities against DENV, HCV, RRV, SINV, WNV, EFV, EBOV, LASV, RABV, VZV, and HSV-1 in immortalized cell cultures (Boonyasuppayakorn et al, 2014;Hulseberg et al, 2019;Mazzon et al, 2019). Niclosamide is an orally bioavailable anthelmintic drug, which inhibits the broadest range of viruses in vitro and, in some cases, in vivo (Cairns et al, 2018;Fang et al, 2013;Huang et al, 2017;Hulseberg et al, 2019;Jurgeit et al, 2012;Kao et al, 2018;Mazzon et al, 2019;Stachulski et al, 2011;Wang et al, 2016;Wu et al, 2004).…”

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

“…Because both viruses are RNA virus depending on RNA-dependent RNA polymerase (RdRp) to replicate, the RdRp inhibitor Arbidol (common name for Umifenovir) approved for influenza in Russia and China has been proposed as a standard care option for COVID-19, mainly based on its mechanism-of-action (MoA) and its effects in treating influenza-associated pneumonia. [5][6][7] Favipiravir, an antiviral drug targeting RdRP, 8 approved in Japan for influenza, has an IC50 of 0.013-0.48 ug/ml for influenza A. Comparing this with the EC50 of 2.7-13.8 ug/ml of Arbidol, 9 we consider Favipiravir might serve as a potential candidate to treat COVID-19.…”