Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

  1. Jesus A. Silvas
  2. Alexander S. Jureka
  3. Anthony M. Nicolini
  4. Stacie A. Chvatal
  5. Christopher F. Basler

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Abstract

Therapeutics targeting replication of SARS coronavirus 2 (SARS-CoV-2) are urgently needed. Coronaviruses rely on host membranes for entry, establishment of replication centers and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we tested small molecule inhibitors that target membrane dynamics or lipid metabolism. Included were inhibitors of the PI3 kinase VPS34, which functions in autophagy, endocytosis and other processes; Orlistat, an inhibitor of lipases and fatty acid synthetase, is approved by the FDA as a treatment for obesity; and Triacsin C which inhibits long chain fatty acyl-CoA synthetases. VPS34 inhibitors, Orlistat and Triacsin C inhibited virus growth in Vero E6 cells and in the human airway epithelial cell line Calu-3, acting at a post-entry step in the virus replication cycle. Of these the VPS34 inhibitors exhibit the most potent activity.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.18.210211: (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

    Experimental Models: Cell Lines
    SentencesResources
    Virus and cell lines: Vero E6 (ATCC# CRL-1586), Calu-3 (ATCC# HTB-55), and Caco-2 (ATCC# HTB-37) were maintained in DMEM (Corning) supplemented with 10% heat inactivated fetal bovine serum (FBS; GIBCO).
    Caco-2
    suggested: None
    For plaque assays, Vero E6 cells were seeded onto a 24-well plate 24 hours before infection.
    Vero E6
    suggested: None
    Cell viability assay: VeroE6 or Calu-3 cells were seeded in 96-well black walled microplates and incubated overnight.
    Calu-3
    suggested: None
    Software and Algorithms
    SentencesResources
    Images were rendered in ZenBlue or Imaris Viewer 9.0.
    Imaris
    suggested: (Imaris, RRID:SCR_007370)
    Median time to death calculations were performed by fitting the Boltzmann sigmoid equation to raw kinetic resistance data in Graphpad Prism.
    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.
    • 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 10.1101/2020.07.18.210211 on bioRxiv