Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2
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Abstract
Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.
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SciScore for 10.1101/2020.08.18.255877: (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
Experimental Models: Cell Lines Sentences Resources Vero E6 African green monkey kidney epithelial cells (selected for high ACE2 expression) were inoculated with SARS CoV-2 (USA_WA1/2020) at multiplicity of infection (MOI) of 0.002 in media and quickly dispensed into assay plates as 25 μL/well. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources The concentration-response curves of re-tested compounds were also plotted using GraphPad Prism 9 (GraphPad Software Inc., San … SciScore for 10.1101/2020.08.18.255877: (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
Experimental Models: Cell Lines Sentences Resources Vero E6 African green monkey kidney epithelial cells (selected for high ACE2 expression) were inoculated with SARS CoV-2 (USA_WA1/2020) at multiplicity of infection (MOI) of 0.002 in media and quickly dispensed into assay plates as 25 μL/well. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources The concentration-response curves of re-tested compounds were also plotted using GraphPad Prism 9 (GraphPad Software Inc., San Diego, CA). GraphPadsuggested: (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: We detected the following sentences addressing limitations in the study:It is worth briefly reflecting on the limitations of the drug repurposing assay approach. A number of small molecules of interest for treating COVID19 that are currently in clinical trials were not hits in our assay. For example, the TMPRSS2 inhibitors camostat and nafamstat are protease inhibitors approved in Japan for treating pancreatitis, and known to inhibit TMPRSS2 (Shrimp et al., 2020). While TMPRSS2 is reported to be a mediator of SARS-CoV-2 cell entry, Vero E6 cells do not express TMPRSS2, so this class of compound are not active in the Vero E6 assay. The drug efflux transporter P-glycoprotein (P-gp) can reduce cellular concentrations of test agents, and as a kidney epithelial cell line, Vero E6 cells likely expresses significant P-gp concentrations, which would reduce activity of P-gp substrates (Robey et al., 2018). Remdesivir itself is a substrate of Pgp (EMA, 2020), and is weaker against SARS-CoV-2 in assays using Vero E6 cells (EC50 > 1 μM) compared with Calu-3 or Huh7 cell lines (EC50 > 50 nM) (2020). These examples highlight the need for careful interpretation and critical follow-up studies after initial high-throughput screening analyses. Importantly, the comprehensive primary screen datasets of this study for approved and investigational drugs, and mechanism-based bioactive compounds have been made publicly available in real-time on the NCATS OpenData Portal (https://opendata.ncats.nih.gov/covid19/index.html) (Brimacombe et al., 2020). These datasets provide...
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: Please consider improving the rainbow (“jet”) colormap(s) used on page 20. 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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