Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

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1. Version published to 10.1002/ddr.21982

   Aug 21, 2022
2. 

   ScreenIT

   Apr 24, 2021

   SciScore for 10.1101/2021.04.20.439992: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Experimental Models: Cell Lines
   Sentences	Resources
   Finally, virus titration was performed on Vero CCL81 cells using standard limiting dilution to determine the 50% tissue culture infectious dose (TCID50) of viral stock47,48. 2.5.	Vero CCL81 suggested: None
   Photomicrographs were taken using the Olympus ix51 inverted microscope and analyzed using the QCapture Pro 6.0 software under 200× magnification (QImaging)49, in order to examine whether celastrol interfered with SARS-CoV-2 cytopathic effects in Vero CCL-81 cells.	Vero CCL-81 suggested: None
   Cell viability: Cytotoxicity of celastrol (Sigma-Aldrich) to Vero CCL-81, Vero CCL-81-ACE2, …

   SciScore for 10.1101/2021.04.20.439992: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Experimental Models: Cell Lines
   Sentences	Resources
   Finally, virus titration was performed on Vero CCL81 cells using standard limiting dilution to determine the 50% tissue culture infectious dose (TCID50) of viral stock47,48. 2.5.	Vero CCL81 suggested: None
   Photomicrographs were taken using the Olympus ix51 inverted microscope and analyzed using the QCapture Pro 6.0 software under 200× magnification (QImaging)49, in order to examine whether celastrol interfered with SARS-CoV-2 cytopathic effects in Vero CCL-81 cells.	Vero CCL-81 suggested: None
   Cell viability: Cytotoxicity of celastrol (Sigma-Aldrich) to Vero CCL-81, Vero CCL-81-ACE2, Calu-3, and Caco-2 was determined using the Alamar Blue Cell Viability protocol (Thermo Scientific, Waltham, USA), according to the manufacturer's instructions.	Vero suggested: None Caco-2 suggested: CLS Cat# 300137/p1665_CaCo-2, RRID:CVCL_0025)
   Interleukin 6 quantification: IL-6 levels were quantified in Caco-2 and Calu-3 cell culture supernatants using the Human DuoSet ELISA assay kit (R&D Systems, USA), according to the manufacturer’s instructions.	Calu-3 suggested: KCLB Cat# 30055, RRID:CVCL_0609)
   Software and Algorithms
   Sentences	Resources
   The signature was submitted to over-representation analysis using Reactome pathways34 and clusterProfiler R package35 to find biological pathways that were enriched due to viral infection, within BH adjusted p-value < 0.05.	Reactome suggested: (Reactome, RRID:SCR_003485) clusterProfiler suggested: (clusterProfiler, RRID:SCR_016884)
   The graphical representation of drug signatures data and scores were generated with pheatmap36 and ggplot2 packages37 in R software38.	ggplot2 suggested: (ggplot2, RRID:SCR_014601)
   Docking analysis was carried out using Autodock Vina43 with exhaustiveness parameter equal to 20.	Autodock suggested: (AutoDock, RRID:SCR_012746)
   Graphical representations of energy results were plotted with ggplot2 R package and molecular model structures were drawn with Pymol44 and Discovery Studio Visualizer® (version-2020)45. 2.3.	Pymol44 suggested: None
   All the experimental data are expressed as mean ± standard error of the mean (SEM), and they were plotted and analyzed using GraphPad Prism 7 software52.	GraphPad Prism suggested: (GraphPad Prism, RRID:SCR_002798)

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   Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

   Despite its potential therapeutic effects, there are still some limitations to the use of celastrol, such as its low solubility that results in poor bioavailability, in vitro and in vivo toxicity, and adverse effects that remain to be evaluated107,108. Celastrol was not cytotoxic to all cell lines tested herein, even at the highest concentration (1000 nM), corroborating other reports using Caco-2 cells109. At 1000 nM, this compound reduced the SARS-CoV-2-cytopathic effect on Vero CCL-81 cells. A recent study using a mouse model of acute toxicity has demonstrated that celastrol is safe even when orally administered at a high dose (62.5 mg/kg body weight)110. Intraperitoneal administration of celastrol (0.25 mg/kg body weight) increases the gamma irradiated-mice survival rate by around 7078. To surpass celastrol toxicity, solubility, and pharmacokinetic issues, several pharmaceutical approaches have been proposed, such as nanoencapsulation, liposomes, and sugar-silica nanoparticles111–113. Celastrol has been considered a lead drug for several human illnesses, but its toxicity to humans remains to be determined64,73,114. To the best of our knowledge, the present study is the pioneer to use the combination between bioinformatic tools and biological approaches to demonstrate that celastrol inhibits the SARS-CoV-2 replication in non-human and human cell lines, and down-regulates IL-6 secretion from infected-human cell lines, reinforcing that celastrol is a potential repurposed drug...

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   Results from TrialIdentifier: No clinical trial numbers were referenced.

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   Results from rtransparent:

   • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
   • No funding statement was detected.
   • No protocol registration statement was detected.

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3. 

   Version published to 10.1101/2021.04.20.439992 on bioRxiv

   Apr 20, 2021