Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro
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Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 (COVID-19), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease (M pro ), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19. Mpro has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of M pro blocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 M pro and diminishes its protease activity. Specifically, TFQ reduces the α-helical content of M pro , which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 M pro . Moreover, the low clinical toxicity of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.
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SciScore for 10.1101/2020.08.14.250258: (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 Time course assay of TFQ: Vero E6 (7 × 104) cells were seeded in 24-well plates and subjected to two modes of drug treatment, one in which cells were pre-treated with drugs for an hour prior to viral infection, and the other without drug pre-treatment. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Melt curve data were plotted using the Boltzmann model to obtain the temperature midpoint of unfolding of the protein using … SciScore for 10.1101/2020.08.14.250258: (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 Time course assay of TFQ: Vero E6 (7 × 104) cells were seeded in 24-well plates and subjected to two modes of drug treatment, one in which cells were pre-treated with drugs for an hour prior to viral infection, and the other without drug pre-treatment. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Melt curve data were plotted using the Boltzmann model to obtain the temperature midpoint of unfolding of the protein using Prism 8.0 software ( Prismsuggested: (PRISM, RRID:SCR_005375)GraphPad) GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Ligand plot of each compound was generated by PDBsum. PDBsumsuggested: (PDBsum, RRID:SCR_006511)Microsoft Excel was used for statistical analyses. Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)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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SciScore for 10.1101/2020.08.14.250258: (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 Virus and cell culture SARS-CoV2 (strain NTU02, GenBank:MT066176.1) was isolated from a COVID-19 patient at National Taiwan University Hospital and grown in Vero E6 cells. Vero E6suggested: RRID:CVCL_XD71)Software and Algorithms Sentences Resources Melt curve data were plotted using the Boltzmann model to obtain the … SciScore for 10.1101/2020.08.14.250258: (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 Virus and cell culture SARS-CoV2 (strain NTU02, GenBank:MT066176.1) was isolated from a COVID-19 patient at National Taiwan University Hospital and grown in Vero E6 cells. Vero E6suggested: RRID:CVCL_XD71)Software and Algorithms Sentences Resources Melt curve data were plotted using the Boltzmann model to obtain the temperature midpoint of unfolding of the protein using Prism 8.0 software ( Prismsuggested: (PRISM, RRID:SCR_005375)GraphPad) GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Ligand plot of each compound was generated by PDBsum. PDBsumsuggested: (PDBsum, RRID:SCR_006511)Microsoft Excel was used for statistical analyses. Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)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 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: We did not find any issues relating to colormaps.
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