Ebola virus requires phosphatidylinositol (3,5) bisphosphate production for efficient viral entry

Qiu, Shirley; Leung, Anders; Bo, Yuxia; Kozak, Robert; Anand, Sai Priya; Warkentin, Corina; Salambanga, Fabiola D.R.; Cui, Jeffrey; Kobinger, Gary P.; Kobasa, Darwyn; Côté, Marceline

doi:10.1016/j.virol.2017.09.028

Cited by 46 publications

(68 citation statements)

References 75 publications

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“…In 2019, orphan drug designation was granted to apilimod in the U.S. for the treatment of follicular lymphoma 88 , with phase I clinical trials ongoing. Notably, it has been reported that apilimod efficiently inhibits EBOV, Lassa virus (LASV), and Marburg virus (MARV) in human cell lines, underscoring its potential broad-spectrum antiviral activity 44,89 . The underlying mechanism for the inhibition of SARS-CoV-2 infection by apilimod is currently not known.…”

Section: Discussionmentioning

confidence: 99%

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Riva

Yuan

Yin

et al. 2020

Preprint

108

111

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The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 . To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDAapproved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

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Section: Discussionmentioning

confidence: 99%

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Riva

Yuan

Yin

et al. 2020

Preprint

108

111

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“…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%

“…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). Apilimod blocks EBOV trafficking to late endosomes (51, 53), which serve as portals for both EBOV and LASV (25, 26, 62-64).…”

Section: Discussionmentioning

confidence: 99%

“…Newer amodiaquine derivatives (59) or synergistic drug pairs containing amodiaquine or niclosamide and another agent could lower the needed doses (23). And while the trafficking inhibitor apilimod is well tolerated and a potent antagonist of EBOV and LASV (51,53,70; also this study), in an early test, it did not protect mice from lethal EBOV challenge (see reference 23), likely due to its inhibition of interleukin 12/23 (IL-12/23) production (reference 61 Among the fusion inhibitors tested, arbidol emerges as a candidate for future consideration, as it shows similar activities against LASV and EBOV and appears, in our assays, somewhat more potent against LASV-and EBOV GP-versus influenza HAmediated fusion and entry. Arbidol is approved and used in China and Russia against influenza and has shown strikingly broad antiviral activity (33,36,71).…”

Section: Discussionmentioning

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

130

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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“…The cell entry of EBOV involves virus binding to the cell surface receptors followed by internalization through macropinocytosis, processing by endosomal proteases, and transport to Niemann–Pick C1 (NPC1; an internal receptor for EBOV) containing endolysosomes. Phosphatidylinositol-3-phosphate 5-kinase is essential for maturation of endosome, a critical step to the EBOV infection ( 145 ). In vitro studies using apilimod, an antagonist of phosphatidylinositol-3-phosphate 5-kinase, showed inhibition of EBOV by blocking the viral particle trafficking to NPC1 containing endolysosomes ( 146 ).…”

Section: Advances In Developing Drugs and Therapies Against Ebovmentioning

confidence: 99%

Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus

et al. 2018

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Ebola virus (EBOV), a member of the family Filoviridae, is responsible for causing Ebola virus disease (EVD) (formerly named Ebola hemorrhagic fever). This is a severe, often fatal illness with mortality rates varying from 50 to 90% in humans. Although the virus and associated disease has been recognized since 1976, it was only when the recent outbreak of EBOV in 2014–2016 highlighted the danger and global impact of this virus, necessitating the need for coming up with the effective vaccines and drugs to counter its pandemic threat. Albeit no commercial vaccine is available so far against EBOV, a few vaccine candidates are under evaluation and clinical trials to assess their prophylactic efficacy. These include recombinant viral vector (recombinant vesicular stomatitis virus vector, chimpanzee adenovirus type 3-vector, and modified vaccinia Ankara virus), Ebola virus-like particles, virus-like replicon particles, DNA, and plant-based vaccines. Due to improvement in the field of genomics and proteomics, epitope-targeted vaccines have gained top priority. Correspondingly, several therapies have also been developed, including immunoglobulins against specific viral structures small cell-penetrating antibody fragments that target intracellular EBOV proteins. Small interfering RNAs and oligomer-mediated inhibition have also been verified for EVD treatment. Other treatment options include viral entry inhibitors, transfusion of convalescent blood/serum, neutralizing antibodies, and gene expression inhibitors. Repurposed drugs, which have proven safety profiles, can be adapted after high-throughput screening for efficacy and potency for EVD treatment. Herbal and other natural products are also being explored for EVD treatment. Further studies to better understand the pathogenesis and antigenic structures of the virus can help in developing an effective vaccine and identifying appropriate antiviral targets. This review presents the recent advances in designing and developing vaccines, drugs, and therapies to counter the EBOV threat.

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Ebola virus requires phosphatidylinositol (3,5) bisphosphate production for efficient viral entry

Cited by 46 publications

References 75 publications

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

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

Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus

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