The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models

  1. Kim M. Stegmann
  2. Antje Dickmanns
  3. Sabrina Gerber
  4. Vella Nikolova
  5. Luisa Klemke
  6. Valentina Manzini
  7. Denise Schlösser
  8. Cathrin Bierwirth
  9. Julia Freund
  10. Maren Sitte
  11. Raimond Lugert
  12. Gabriela Salinas
  13. Toni Luise Meister
  14. Stephanie Pfaender
  15. Dirk Görlich
  16. Bernd Wollnik
  17. Uwe Groß
  18. Matthias Dobbelstein

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Abstract

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  1. Version published to 10.1016/j.virusres.2021.198469
  2. ScreenIT

    SciScore for 10.1101/2020.07.18.210013: (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.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Experimental Model And Methods: Quantification And Statistical Analysis: Statistical testing was performed using Graph Pad Prism 6 (RRID:SCR_002798).
    Graph Pad Prism
    detected: 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: We detected the following sentences addressing limitations in the study:
    Having said this, a number of caveats still apply. Firstly, the dose of MTX that would be needed for antiviral treatment is probably higher than the typical dose taken by patients for the purpose of long-term anti-inflammation treatment. Plasma concentrations in patients treated for rheumatoid arthritis, typically taking 7.5 mg/week for months or even years, are only around 25 nM (Hornung et al., 2008), which is unlikely to interfere with virus replication. On the other hand, when applying high-dose therapies, up to 1000 μM plasma concentrations are achievable (Comandone et al., 2005), i.e. 1000-fold more than what would be required for the antiviral effect in our study. Under such circumstances, a limiting toxicity would consist in mucositis, which is often observed when treating leukemia with high-dose MTX in a pediatric setting (den Hoed et al., 2015). Antiviral activities of MTX would presumably require an intermediate shortterm dose for a week or two. The antiviral concentration of MTX (> 1 μM) is achieved, for instance, by single intramuscular application of 50 mg MTX, which is a common procedure to induce abortions at early stages of pregnancy (Creinin and Vittinghoff, 1994). In this setting, tolerable side effects were reported, e.g. transient nausea, diarrhea, and headache (Creinin and Krohn, 1997). This comparison, on the other hand, makes it very clear that antiviral doses of MTX are contraindicated in pregnant women. A clinical study using nanoparticle-coupled MTX...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04425252CompletedSafety and Anti-coronavirus Response of Suppression of Host …
    NCT04352465Not yet recruitingEfficacy and Safety of MTX-loaded Nanoparticles to Treat Sev…

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

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 33. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.
    • Thank you for including a protocol registration statement.

    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.

  3. Version published to 10.1101/2020.07.18.210013v1 on bioRxiv