Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting

Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan C.; Ho, Chi-Lee C.; Retterer, Cary; Gharaibeh, Dima N.; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A.; Clubb, Robert T.; Cohen, Stanley N.; Gupta, Vivek; Martchenko, Mikhail

doi:10.1038/srep13476

Cited by 40 publications

(80 citation statements)

References 47 publications

(62 reference statements)

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“…This hypothesis was strengthened by the anti‐DT effects of these compounds. In addition, both of these compounds were described previously as antitoxin drugs—amodiaquine inhibits cathepsin B, a lysosomal protease implicated in vesicle acidification—and has broad spectrum applications, while bepridil was previously shown to protect cells from anthrax toxin, as well as DT …”

Section: Resultsmentioning

confidence: 99%

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

et al. 2018

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Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1-induced Rac1 degradation, and five also showed a protective effect against CNF1-induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1-based diseases.

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Section: Resultsmentioning

confidence: 99%

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

et al. 2018

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“…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%

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

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

128

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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“…A recent review reported that AQ also inhibits the pathogenicity of ZIKV at similar concentrations to those for EBOV . It was recently reported that AQ inhibits host cathepsin B protein, thereby preventing entry of viruses such as EBOV into host cells . It is likely that AQ acts on this host protein to protect host cells from infection by ZIKV.…”

Section: Discussionmentioning

confidence: 99%

The antimalarial drug amodiaquine possesses anti‐ZIKA virus activities

Han

Mésplède

et al. 2018

Journal of Medical Virology

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Zika virus (ZIKV) outbreak has emerged as a global health threat, particularly in tropical areas, over the past few years. No antiviral therapy or vaccine is available at present. For these reasons, repurposing clinically approved drugs against ZIKV infection may provide rapid and cost-effective global health benefits. Here, we explored this strategy and screened eight FDA-approved drugs for antiviral activity against ZIKV using a cell-based assay. Our results show that the antimalarial drug amodiaquine has anti-ZIKV activity with EC at low micromolar concentrations in cell culture. We further characterized amodiaquine antiviral activity against ZIKV and found that it targets early events of the viral replication cycle. Altogether, our results suggest that amodiaquine may be efficacious for the treatment of ZIKV infection.

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Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting

Cited by 40 publications

References 47 publications

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

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

The antimalarial drug amodiaquine possesses anti‐ZIKA virus activities

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