Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine

  1. Marion Plaze
  2. David Attali
  3. Matthieu Prot
  4. Anne-Cécile Petit
  5. Michael Blatzer
  6. Fabien Vinckier
  7. Laurine Levillayer
  8. Florent Perin-Dureau
  9. Arnaud Cachia
  10. Gérard Friedlander
  11. Fabrice Chrétien
  12. Etienne Simon-Loriere
  13. Raphaël Gaillard

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Abstract

Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. In this study, we describe the in vitro testing of CPZ against a SARS-CoV-2 isolate in monkey and human cells. We evidenced an antiviral activity against SARS-CoV-2 with an IC50 of ∼10μM. Because of its high biodistribution in lung, saliva and brain, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine. This extrapolation is in line with our observations of a higher prevalence of symptomatic and severe forms of COVID-19 infections among health care professionals compared to patients in psychiatric wards. These preclinical findings support the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.05.079608: (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
    Cell culture and virus isolates: Vero E6 cells (African green monkey kidney epithelial cells, ATCC, CRL-1586) were maintained in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal bovine serum (FBS) and 5 units/mL penicillin and 5 μg/mL streptomycin at 37°C with 5% CO2.
    Vero E6
    suggested: None
    A549-ACE2 cells (adenocarcinomic human alveolar basal epithelial cells, transduced to express the human Angiotensin-converting enzyme 2 (ACE2), kind gift of Pr. O. Schwartz, Institut Pasteur, Paris France) were maintained in DMEM containing 10% FBS, 5 units/mL penicillin and 5 μg/mL streptomycin and 40 µg/mL blasticidin at 37°C with 5% CO2.
    A549-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    IC50 values were fitted using four-parameter dose response curves in GraphPad prism v8.4.2.
    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04366739Not yet recruitingRepurposing of Chlorpromazine in Covid-19 Treatment

    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 10.1101/2020.05.05.079608 on bioRxiv