Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

  1. Einat. B. Vitner
  2. Roy Avraham
  3. Hagit Achdout
  4. Hadas Tamir
  5. Avi Agami
  6. Lilach Cherry
  7. Yfat Yahalom-Ronen
  8. Boaz Politi
  9. Noam Erez
  10. Sharon Melamed
  11. Nir Paran
  12. Tomer Israely

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Abstract

The need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.

One Sentence Summary

An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.18.103283: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    CCL-81™), Vero E6 (ATCC® CRL-1586™), Neuro-2a (ATCC® CCL-131™) and Madin-Darby Canine Kidney (MDCK) cells (ATCC® CCL-34™) obtained from the American Type Culture Collection (Summit Pharmaceuticals International, Japan).
    Neuro-2a
    suggested: None
    WNV virus (NY-99, ATCC® VR-1507™) was used.
    NY-99
    suggested: RRID:CVCL_NY99)
    Titer of stock was determined by plaque assay on Vero E6 cells monolayers.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Inhibition of Sindbis virus in cell-culture: Vero or Neuro-2a cells were seeded at a density of 3 × 104 cells per well in 96-well plates.
    Vero
    suggested: RRID:CVCL_ZW93)
    Inhibition of Influenza virus in cell-culture: MDCK cells were seeded at a density of 5 × 105 cells per well in 6-well plates.
    MDCK
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Studies in mice: C57BL/6 mice (21-days old) were infected intraperitoneally (i.p) with SVNI (15 PFU/mouse).
    C57BL/6
    suggested: None
    Software and Algorithms
    SentencesResources
    Evaluation of the half maximal inhibitory concentration (IC50) was performed by GraphPad Prism 6.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Samples were collected using Fortessa Flowcytometer (BD Biosciences) and analyzed with FlowJo software (Treestar)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.05.18.103283v1 on bioRxiv