Repurposing of Miglustat to inhibit the coronavirus Severe Acquired Respiratory Syndrome SARS-CoV-2

  1. Sreejith Rajasekharan
  2. Rafaela Milan Bonotto
  3. Yvette Kazungu
  4. Lais Nascimento Alves
  5. Monica Poggianella
  6. Pamela Martinez Orellana
  7. Natasa Skoko
  8. Sulena Polez
  9. Alessandro Marcello

Reviewed by

Read the full article

Listed in

Log in to save this article

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.

Article activity feed

  1. ScreenIT

    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 Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line AuthenticationContamination: Cells were routinely tested for mycoplasma contamination.

    Table 2: Resources

    Antibodies
    SentencesResources
    The anti-his antibody (monoclonal #8722 Sigma) was used at 1/2000 concentration for immunoblot.
    anti-his
    suggested: (LSBio (LifeSpan Cat# LS-C67917-2000, RRID:AB_1817500)
    Experimental Models: Cell Lines
    SentencesResources
    ATCC-1586) HEK 293T (ATCC CRL-3216), A549 (ATCC CCL-185),
    A549
    suggested: None
    U2OS (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.
    U2OS
    suggested: None
    Huh7
    suggested: None
    Plaque 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 E6
    suggested: None
    Plasmid was transfected in 293T cells and cell extracts and supernatants were harvested 24 hours post-transfection.
    293T
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    ATCC-1586) HEK 293T (ATCC CRL-3216), A549 (ATCC CCL-185),
    ATCC-1586 ) HEK 293T
    suggested: None
    Software and Algorithms
    SentencesResources
    The half maximal effective concentration (EC50) and cytotoxic concentration (CC50) were calculated using GraphPad Prism Version 7.
    GraphPad Prism
    suggested: (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.

    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 10.1101/2020.05.18.101691v1 on bioRxiv