Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

  1. Intikhab alam
  2. Allan Kamau
  3. Maxat Kulmanov
  4. Stefan T. Arold
  5. Arnab Pain
  6. Takashi Gojobori
  7. Carlos M. Duarte

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 spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells 1 . The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1–specific neutralizing antibodies to inhibit SARS-CoV-2 3 . Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS) 4-6 , the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7,8 . However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride 9,10 ) or the PBM (SB203580 5 ), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo . Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi -identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.02.17.952895: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    AAMG uses sequence-based BLAST to UniProtKB (www.uniprot.org),
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    UniProtKB
    suggested: (UniProtKB, RRID:SCR_004426)
    KEGG (www.kegg.jp) and also Protein Family (PFam) domain detection using InterPro (www.ebi.ac.uk/interpro).
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    PFam
    suggested: (Pfam, RRID:SCR_004726)
    InterPro
    suggested: (InterPro, RRID:SCR_006695)
    Predicted Gene Ontology (GO) terms with a confidence score from DeepGOPlus were visualized using QuickGO (https://www.ebi.ac.uk/QuickGO/) for SARS-CoV-2 specific gene clusters.
    QuickGO
    suggested: (QuickGO, RRID:SCR_004608)
    s Structure based prediction of function: ProtParam (https://web.expasy.org/cgi-bin/protparam/protparam) was used for calculating protein features.
    ProtParam
    suggested: (ProtParam Tool, RRID:SCR_018087)
    Phobius (http://phobius.sbc.su.se/) and SignalP-5.0 were used for prediction of transmembrane regions and signal peptides 28.
    http://phobius.sbc.su.se/
    suggested: (Phobius, RRID:SCR_015643)

    Results from OddPub: Thank you for sharing your code.

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 14. 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:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • 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 10.1101/2020.02.17.952895 on bioRxiv