Targeting the Pentose Phosphate Pathway for SARS-CoV-2 Therapy

  1. Denisa Bojkova
  2. Rui Costa
  3. Philipp Reus
  4. Marco Bechtel
  5. Mark-Christian Jaboreck
  6. Ruth Olmer
  7. Ulrich Martin
  8. Sandra Ciesek
  9. Martin Michaelis
  10. Jindrich Cinatl

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Abstract

SARS-CoV-2 is causing the coronavirus disease 2019 (COVID-19) pandemic, for which effective pharmacological therapies are needed. SARS-CoV-2 induces a shift of the host cell metabolism towards glycolysis, and the glycolysis inhibitor 2-deoxy-d-glucose (2DG), which interferes with SARS-CoV-2 infection, is under development for the treatment of COVID-19 patients. The glycolytic pathway generates intermediates that supply the non-oxidative branch of the pentose phosphate pathway (PPP). In this study, the analysis of proteomics data indicated increased transketolase (TKT) levels in SARS-CoV-2-infected cells, suggesting that a role is played by the non-oxidative PPP. In agreement, the TKT inhibitor benfooxythiamine (BOT) inhibited SARS-CoV-2 replication and increased the anti-SARS-CoV-2 activity of 2DG. In conclusion, SARS-CoV-2 infection is associated with changes in the regulation of the PPP. The TKT inhibitor BOT inhibited SARS-CoV-2 replication and increased the activity of the glycolysis inhibitor 2DG. Notably, metabolic drugs like BOT and 2DG may also interfere with COVID-19-associated immunopathology by modifying the metabolism of immune cells in addition to inhibiting SARS-CoV-2 replication. Hence, they may improve COVID-19 therapy outcomes by exerting antiviral and immunomodulatory effects.

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  1. Version published to 10.3390/metabo11100699
  2. ScreenIT

    SciScore for 10.1101/2020.08.19.257022: (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

    Antibodies
    SentencesResources
    Primary antibody was detected with a peroxidase-conjugated anti-rabbit secondary antibody (1:1000, Dianova), followed by addition of AEC substrate.
    anti-rabbit
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Cell culture and virus production: Caco-2 cells, a colon carcinoma derived cell line, was maintained in MEM (Minimal Essential Medium) containing 10% (v/v) foetal bovine serum,10,000 U penicillin/streptomycin and 2% (v/v) L-glutamine (Sigma Aldrich, Germany).
    Caco-2
    suggested: None
    Software and Algorithms
    SentencesResources
    Proteins derived from Caco-2 cells infected with SARS-CoV-2 after 24 h post infection and matching search terms “glycolysis” and “pentose phosphate pathway” in KEGG database were selected for further analysis.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    GraphPad Prism 8 software was used to plot the graphical representation and to perform statistical analysis.
    GraphPad
    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

  3. Version published to 10.1101/2020.08.19.257022v1 on bioRxiv