Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity – opportunity for repurposed chemotherapy of COVID-19 infection

  1. Maryam Al-Motawa
  2. Hafsa Abbas
  3. Patrick Wijten
  4. Alberto de la Fuente
  5. Mingzhan Xue
  6. Naila Rabbani
  7. Paul J. Thornalley

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produced an urgent requirement and search for improved treatments whilst effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. For arginine residues of the SARS-CoV-2 predicted to be in functional domains, we examined which are activated towards modification by MG – residues with predicted or expected low pK a by neighbouring group in interactions. We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae : SARS-COV and MERS. Finally, we identified drugs which increase cellular MG concentration to virucidal levels: antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.04.07.029488: (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
    Reagents and Chemicals: Doxorubicin, Paclitaxel, monoclonal anti-Glo1 antibody (rat), anti-Rat IgG (whole molecule)–Biotin conjugate, D-Lactic dehydrogenase were purchased from Sigma-Aldrich (Poole, Dorset, UK).
    anti-Glo1
    suggested: (Sigma-Aldrich Cat# SAB1100241, RRID:AB_10606523)
    anti-Rat IgG
    suggested: None
    D-Lactic dehydrogenase
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The HEK293 cell line was purchased from the American Tissue Culture Collection (ATCC, Virginia, USA).
    HEK293
    suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)
    Software and Algorithms
    SentencesResources
    Sequences of reviewed proteins of the human proteome, 18,821 – excluding fetal proteins, were obtained from the UniProtKB database (www.uniprot.org).
    UniProtKB
    suggested: (UniProtKB, RRID:SCR_004426)
    To identify similar arginines residues in SARS-CoV and MERS proteins, we used the Clustal Omega software on-line (Madeira et al., 2019).
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)

    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.

    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 10.1101/2020.04.07.029488 on bioRxiv