Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19
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Abstract
Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 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, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which 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 ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. 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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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 Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources MERS-CoV infection was detected using rabbit anti-MERS-CoV S antibodies, and cell viability was evaluated by Hoechst 33342 staining. anti-MERS-CoV Ssuggested: NoneExperimental Models: Cell Lines Sentences Resources 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 … 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 Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources MERS-CoV infection was detected using rabbit anti-MERS-CoV S antibodies, and cell viability was evaluated by Hoechst 33342 staining. anti-MERS-CoV Ssuggested: NoneExperimental Models: Cell Lines Sentences Resources 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-3suggested: ATCC Cat# HTB-55, RRID:CVCL_0609)Viral titers were determined by plaque assays in Vero cells as described [16]. Verosuggested: 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-E6suggested: NoneSoftware and Algorithms Sentences Resources 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. MESHsuggested: (MeSH, RRID:SCR_004750)The information on approval status for drugs was retrieved from DrugBank, version 5.0.7 [22]. DrugBanksuggested: (DrugBank, RRID:SCR_002700)The expected responses were calculated based on the zero interaction potency (ZIP) reference model using SynergyFinder version 2 [17]. SynergyFindersuggested: (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.
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