Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections
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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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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 Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources 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-2asuggested: NoneWNV virus (NY-99, ATCC® VR-1507™) was used. NY-99suggested: RRID:CVCL_NY99)Titer of stock was determined by plaque assay on Vero E6 cells monolayers. Vero E6suggested: RRID:CVCL_XD71)Inhibition of … 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 Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources 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-2asuggested: NoneWNV virus (NY-99, ATCC® VR-1507™) was used. NY-99suggested: RRID:CVCL_NY99)Titer of stock was determined by plaque assay on Vero E6 cells monolayers. Vero E6suggested: 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. Verosuggested: 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. MDCKsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources Studies in mice: C57BL/6 mice (21-days old) were infected intraperitoneally (i.p) with SVNI (15 PFU/mouse). C57BL/6suggested: NoneSoftware and Algorithms Sentences Resources Evaluation of the half maximal inhibitory concentration (IC50) was performed by GraphPad Prism 6. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Samples were collected using Fortessa Flowcytometer (BD Biosciences) and analyzed with FlowJo software (Treestar) FlowJosuggested: (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.
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