Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening
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Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C like protease (3CL pro ), or main protease (M pro ) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high throughput screening (qHTS) of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CL pro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CL pro have been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC 50 = 0.26 µM), Hydroxocobalamin (IC 50 = 3.29 µM), Suramin sodium (IC 50 = 6.5 µM), Z-DEVD-FMK (IC 50 = 6.81 µM), LLL-12 (IC 50 = 9.84 µM), and Z-FA-FMK (IC 50 = 11.39 µM) are the most potent 3CL pro inhibitors. The activities of anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CL pro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients, and as starting points for chemistry optimization for new drug development.
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SciScore for 10.1101/2020.07.17.207019: (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 In brief, high ACE2 expressing Vero E6 cells were inoculated with SARS-CoV-2 (USA_WA1/2020) at 0.002 M.O.I. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources MIPE 5.0 library includes 2480 compounds that are mixed with approved and investigational compounds, and mechanistic based compounds focusing on oncology MIPEsuggested: (MIPE, RRID:SCR_003065)Concentration-response curves were fitted and IC50 values of confirmed … SciScore for 10.1101/2020.07.17.207019: (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 In brief, high ACE2 expressing Vero E6 cells were inoculated with SARS-CoV-2 (USA_WA1/2020) at 0.002 M.O.I. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources MIPE 5.0 library includes 2480 compounds that are mixed with approved and investigational compounds, and mechanistic based compounds focusing on oncology MIPEsuggested: (MIPE, RRID:SCR_003065)Concentration-response curves were fitted and IC50 values of confirmed compounds were calculated using the GraphPad Prism software (San Diego, CA, USA). GraphPad Prismsuggested: (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: 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: 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.
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