Repurposing of Miglustat to inhibit the coronavirus Severe Acquired Respiratory Syndrome SARS-CoV-2
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Abstract
Repurposing clinically available drugs to treat the new coronavirus disease COVID-19 is an urgent need in these early stages of the SARS-CoV-2 pandemic, when very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated for SARS-CoV-2 at concentrations achievable in the plasma by current clinical regimens without cytotoxicity. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious virus. The mechanism resides in the inhibitory activity towards α-glucosidases that are involved in early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. The wealth of available data on the clinical use of Miglustat for the treatment of lysosomal storage disorders and the antiviral properties against SARS-CoV-2 make it an ideal candidate for drug repurposing.
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SciScore for 10.1101/2020.05.18.101691: (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 Contamination: Cells were routinely tested for mycoplasma contamination. Table 2: Resources
Antibodies Sentences Resources The anti-his antibody (monoclonal #8722 Sigma) was used at 1/2000 concentration for immunoblot. anti-hissuggested: (LSBio (LifeSpan Cat# LS-C67917-2000, RRID:AB_1817500)Experimental Models: Cell Lines Sentences Resources ATCC-1586) HEK 293T (ATCC CRL-3216), A549 (ATCC CCL-185), A549suggested: NoneU2OS (ATCC HTB-96) and human hepatocarcinoma Huh7 cells kindly provided by Ralf Bartenschlager (University … SciScore for 10.1101/2020.05.18.101691: (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 Contamination: Cells were routinely tested for mycoplasma contamination. Table 2: Resources
Antibodies Sentences Resources The anti-his antibody (monoclonal #8722 Sigma) was used at 1/2000 concentration for immunoblot. anti-hissuggested: (LSBio (LifeSpan Cat# LS-C67917-2000, RRID:AB_1817500)Experimental Models: Cell Lines Sentences Resources ATCC-1586) HEK 293T (ATCC CRL-3216), A549 (ATCC CCL-185), A549suggested: NoneU2OS (ATCC HTB-96) and human hepatocarcinoma Huh7 cells kindly provided by Ralf Bartenschlager (University of Heidelberg, Germany) were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Gibco) and antibiotics. U2OSsuggested: NoneHuh7suggested: NonePlaque assay was performed by incubating dilutions of SARS-CoV-2 on Vero E6 monolayers at 37 °C for 1 hour, which were then washed with phosphate buffered saline (PBS) and overlaid with DMEM 2% FBS containing 1.5% carboxymethylcellulose for 3 days. Vero E6suggested: NonePlasmid was transfected in 293T cells and cell extracts and supernatants were harvested 24 hours post-transfection. 293Tsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources ATCC-1586) HEK 293T (ATCC CRL-3216), A549 (ATCC CCL-185), ATCC-1586 ) HEK 293Tsuggested: NoneSoftware and Algorithms Sentences Resources The half maximal effective concentration (EC50) and cytotoxic concentration (CC50) were calculated using GraphPad Prism Version 7. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)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.
- No funding statement was detected.
- No protocol registration statement was detected.
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