Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19

  1. Meehyun Ko
  2. So Young Chang
  3. Soo Young Byun
  4. Aleksandr Ianevski
  5. Inhee Choi
  6. Anne-Laure Pham Hung d’Alexandry d’Orengiani
  7. Denis E. Kainov
  8. David Shum
  9. Ji-Young Min
  10. Marc P. Windisch

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Abstract

Therapeutic options for coronavirus remain limited. To address this unmet medical need, we screened 5,406 compounds, including United States Food and Drug Administration (FDA)- approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6. Time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI>100), atovaquone, an anti-malarial (TI>34), and ciclosonide, an inhalable corticosteroid (TI>6). Furthermore, utilizing the severe acute respiratory syndrome CoV-2 (SARS-CoV-2), combinations of remedesivir with selected dugs were evaluated, which identified ciclosonide and nelfinavir to be additive and synergistic drugs in vitro , respectively. Together, we screened FDA-approved drugs using patient-derived MERS-CoV, triaged hits to discriminate between early and late viral life cycle inhibitors, confirmed selected drugs using SARS-CoV-2, and demonstrated the added value of selected medications in combination with remedesivir. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.

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  1. Version published to 10.1101/2020.02.25.965582v3 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.02.25.965582: (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
    MERS-CoV infection was detected using rabbit anti-MERS-CoV S antibodies, and cell viability was evaluated by Hoechst 33342 staining.
    anti-MERS-CoV S
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Calu-3 cells (ATCC HTB-55; Manassas, VA, USA) were maintained at 37°C with 5% CO2 in Eagle’s Minimum Essential Medium (ATCC, Manassas, VA, USA) with 10% heat-inactivated fetal bovine serum and 1X antibiotic-antimycotic solution (Gibco/Thermo Fisher Scientific, Waltham, MA, USA).
    Calu-3
    suggested: ATCC Cat# HTB-55, RRID:CVCL_0609)
    Viral titers were determined by plaque assays in Vero cells as described [16].
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    Briefly, the virus was amplified in Vero-E6 cells incubated in DMEM containing Pen/Strep and 0.2% bovine serum albumin.
    Vero-E6
    suggested: None
    Software and Algorithms
    SentencesResources
    2.5 Pharmacological action clustering: The information regarding pharmacological actions of each compound was compiled by using ChemIDPlus and MESH databases [20,21] and information provided by the vendors.
    MESH
    suggested: (MeSH, RRID:SCR_004750)
    The information on approval status for drugs was retrieved from DrugBank, version 5.0.7 [22].
    DrugBank
    suggested: (DrugBank, RRID:SCR_002700)
    The expected responses were calculated based on the zero interaction potency (ZIP) reference model using SynergyFinder version 2 [17].
    SynergyFinder
    suggested: (SynergyFinder, RRID:SCR_019318)

    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 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: Please consider improving the rainbow (“jet”) colormap(s) used on page 23. 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:
    • 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.

  3. Version published to 10.1101/2020.02.25.965582v2 on bioRxiv
  4. Version published to 10.1101/2020.02.25.965582v1 on bioRxiv