Identification of Combinations of Approved Drugs With Synergistic Activity Against Ebola Virus in Cell Cultures

Dyall, Julie; Nelson, Elizabeth A.; DeWald, Lisa Evans; Guha, Rajarshi; Hart, Brit J.; Zhou, Huanying; Postnikova, Elena; Logue, James; Vargas, Walter M.; Gross, Robin; Michelotti, Julia; Deiuliis, Nicole; Bennett, Richard S.; Crozier, Ian; Holbrook, Michael R.; Morris, Patrick J.; Klumpp‐Thomas, Carleen; McKnight, Crystal; Mierzwa, Tim; Shinn, Paul; Glass, Pamela J.; Johansen, Lisa M.; Jahrling, Peter B.; Hensley, Lisa E.; Olinger, Gene G.; Thomas, Craig J.; White, Judith M.

doi:10.1093/infdis/jiy304

Cited by 50 publications

(86 citation statements)

References 33 publications

(46 reference statements)

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“…For three drugs, clomiphene, sertraline, and toremifene, the IC 50 values for LASV were ϳ3to 6-fold greater than those for EBOV, indicating that these drugs are more potent against EBOV. It is noteworthy that these three drugs are cationic amphiphilic drugs (CADs), which may be especially active against EBOV (19,20,23,40).…”

Section: Resultsmentioning

confidence: 99%

“…We began this study by comparing the ability of eight drugs to inhibit LASV and EBOV GP-mediated infection. All eight are orally available, room temperature-stable small molecules that block EBOV entry (18-20, 22, 23, 40, 50) and target entry processes also used by LASV (20)(21)(22)(23)(51)(52)(53). Six are approved for clinical use and two are in advanced clinical testing.…”

Section: Discussionmentioning

confidence: 99%

“…Two drugs that impair endosome acidification, needed for the entry of both viruses (25, 49)amodiaquine (an antimalarial) and niclosamide (an anthelminthic)-also showed similar potencies against these two viral GPs in our direct comparative tests. Both have been shown, albeit not in direct comparative studies, to inhibit many pathogens that enter cells by endocytosis (21)(22)(23)(57)(58)(59)(60). The fourth drug with similar activity against both viruses is apilimod, which inhibits PIKfyve, an enzyme required for late endosome maturation (51,53,61) and EBOV entry (27).…”

Section: Discussionmentioning

confidence: 99%

“…The other three drugs-clomiphene, toremifene, and sertraline-showed ϳ3to 6-fold greater activity against EBOV GP-than LASV GP-mediated entry. They are CADs that block EBOV infections (19,20,22,23,40) and cause cholesterol accumulation in late endosomes, mimicking effects of dysfunctional NPC1, the EBOV receptor (27,28,65). Since LASV also enters cells through late endosomes (31), CADs may interfere with LASV entry due to general impairments of late endosome function.…”

Section: Discussionmentioning

confidence: 99%

“…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. When this strategy was employed, many FDA-approved compounds with repurposing potential were identified that showed inhibitory effects against EBOV (18)(19)(20)(21)(22)(23)(24). Many of these are thought to act upon the entry stages of EBOV infection.…”

mentioning

confidence: 99%

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

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

126

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

126

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Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection

Rogers

Shtanko

Stunz

et al. 2020

Journal of Leukocyte Biology

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Many acute viral infections target tissue M s, yet the mechanisms of M-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal M s restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection. With peritoneal cell populations infected with the filovirus, wild-type (WT) Ebola virus (EBOV), or a BSL2 model virus, recombinant vesicular stomatitis virus encoding Ebola virus glycoprotein (rVSV/EBOV GP), we examined the mechanism conferring protection. Here, we demonstrate that restricted virus replication in M s required CD154/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-production, which induced proinflammatory polarization of M s, protecting the cells from infection. These CD40-dependent events protected mice against virus challenge. CD40 −/− mice were exquisitely sensitive to intraperitoneal challenge with a dose of rVSV/EBOV GP that was sublethal to CD40 +/+ mice, exhibiting viremia within 12 h of infection and rapidly succumbing to infection. This study identifies a previously unappreciated role for M-intrinsic CD40 signaling in controlling acute virus infection.

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Mechanisms of Immune Evasion by Ebola Virus

Bhattacharyya

2021

Microbial Pathogenesis

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Identification of Combinations of Approved Drugs With Synergistic Activity Against Ebola Virus in Cell Cultures

Cited by 50 publications

References 33 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

Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection

Mechanisms of Immune Evasion by Ebola Virus

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