The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models

  1. Scott P. Davies
  2. Courtney J. Mycroft-West
  3. Isabel Pagani
  4. Harriet J. Hill
  5. Yen-Hsi Chen
  6. Richard Karlsson
  7. Ieva Bagdonaite
  8. Scott E. Guimond
  9. Zania Stamataki
  10. Marcelo Andrade De Lima
  11. Jeremy E. Turnbull
  12. Zhang Yang
  13. Elisa Vicenzi
  14. Mark A. Skidmore
  15. Farhat L. Khanim
  16. Alan Richardson

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Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.

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  1. Version published to 10.3389/fphar.2021.660490
  2. Version published to 10.1101/2021.01.10.426114v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.01.10.426114: (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
    The beads were washed twice with RIPA and once with Tris-buffered saline before being separated on a 4-12% SDS-PAGE gel, transferred to PVDF and proteins detected with anti-FLAG (1/1000) or anti-His (0.08 μg/ml) antibodies.
    anti-FLAG
    suggested: (Advanced Targeting Systems Cat# AB-450-1000, RRID:AB_10584603)
    anti-His
    suggested: None
    Cells were then blocked in PBS containing 10% FBS and stained with rabbit anti-SARS-CoV-2 spike protein, subunit 1 (The Native Antigen Company), followed by Alexa Fluor 555-conjugated goat anti-rabbit IgG secondary antibody (Invitrogen, Thermo Fisher Scientific)
    anti-SARS-CoV-2 spike protein , subunit 1
    suggested: None
    Alexa Fluor 555-conjugated goat
    suggested: None
    IgG secondary antibody ( Invitrogen , Thermo Fisher Scientific)
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    After incubating at room temperature for 30 minutes, the transfection mix was mixed with 10 volumes of well dispersed HEK-293 cells (300,000 cells/mL) in 10% FCS/DMEM without antibiotics and, 25 μL plated per well of white 384 well plates.
    HEK-293
    suggested: None
    Alternatively, Vero cells were incubated with compounds together with a virus suspension containing 50 PFU (co-treatment) in a total volume of 300 μl complete medium for 1 hour.
    Vero
    suggested: None
    Software and Algorithms
    SentencesResources
    37-2900) and Anti-FLAG from Cell Signalling Technology (#2368).
    Cell Signalling Technology
    suggested: None
    First-order differential plots were calculated after smoothing (Savitzky-Golay, 9 neighbours, 2nd-order polynomial) using Prism 8 (GraphPad).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The peak maxima of the first-order differential plots were determined with MatLab software (R20018a, MathWorks) and used to calculate the change in Tm in the presence of fibrates.
    MatLab
    suggested: (MATLAB, RRID:SCR_001622)

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04517396Enrolling by invitationFEnofibRate as a Metabolic INtervention for COVID-19
    NCT04661930RecruitingFenofibrate for Patients With COVID-19 Requiring Hospitaliza…

    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.
    • 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.

  4. Version published to 10.1101/2021.01.10.426114v1 on bioRxiv