Use of Favipiravir to Treat Lassa Virus Infection in Macaques

Rosenke, Kyle; Feldmann, Heinz; Westover, Jonna B.; Hanley, Patrick W.; Martellaro, Cynthia; Feldmann, Friederike; Saturday, Greg; Lovaglio, Jamie; Scott, Dana; Furuta, Yoshihiko; Komeno, Takashi; Gowen, Brian B.; Safronetz, David

doi:10.3201/eid2409.180233

Cited by 81 publications

(54 citation statements)

References 14 publications

(28 reference statements)

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“…Promising new compounds against LASV have been identified (6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), but the limited geographical endemicity of LASV, its inefficient person-to-person transmission, and low reinfection rates make the prospect of collecting adequate clinical trial data on new drugs challenging. Thus, a practical approach to more expeditiously grow the arsenal of drugs against these highly pathogenic viruses is to screen approved drugs for antiviral activity.…”

mentioning

confidence: 99%

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

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

129

138

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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...

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mentioning

confidence: 99%

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

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

129

138

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“…For example, the influenza RNA dependent RNA polymerase inhibitor, favipiravir (available in Japan), exhibits broad spectrum RNA virus activity with efficacy against the polymerase of Ebola and Lassa fever [16][17][18]. These activities of favipiravir highlight the potential for targeting a protein universal to RNA viruses.…”

Section: Antivirals With Broad Spectrum Propertiesmentioning

confidence: 99%

Broad-Spectrum Antiviral Agents: A Crucial Pandemic Tool

Adalja

Inglesby

2019

Expert Review of Anti-infective Therapy

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“…Anti-arenavirus drugs. Ribavirin is used under compassionate use protocols for the treatment of LassaF [97,112], while recently favipiravir was evaluated and found to enhance survival in cynomolgus (crab-eating) macaques [125]. A further interesting compound is LHF 535, an entry inhibitor targeting arenaviral GP2 [91].…”

Section: Arenaviridaementioning

confidence: 99%

“…Broad-spectrum antivirals on the other hand show significant activity against several members of the same or distinct virus families, allowing the empirical treatment of severe viral infections prior to positive diagnosis of the viral agent. Leading examples are at his point the pyrazinecarboxamide compounds T-705 (favipiravir; [2,7,48]), T-1105 and T-1106, which are broad-spectrum viral RNA polymerase inhibitors, initially developed for the treatment of influenza virus, and found effective against bunyaviruses [21,54,59], alphaviruses [1], filoviruses [13] arenaviruses [125], paramyxoviruses [29], and flaviviruses [128]. A favipiravir resistance mechanism in influenza virus has been described [52].…”

Section: Synergy Through Combination and The Use Of Broad-spectrum Anmentioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

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The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Use of Favipiravir to Treat Lassa Virus Infection in Macaques

Cited by 81 publications

References 14 publications

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

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

Broad-Spectrum Antiviral Agents: A Crucial Pandemic Tool

Antivirals in medical biodefense

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