Geneticin shows selective antiviral activity against SARS-CoV-2 by interfering with programmed −1 ribosomal frameshifting
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SciScore for 10.1101/2022.03.08.483429: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication Authentication: The ff99+bsc0+χOL3 force field was used for MD simulation since this is the most validated and recommended FFs for RNA system (31). Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For experiments with the different SARS-CoV-2 variant and analogues of geneticin, Vero-E6 cells were overlaid instead with 0.4% avicel gp3515 in medium containing 2.5% FBS. Vero-E6suggested: NoneAntiviral assay in Calu3 cells: Calu-3 cells (4 x 104 cells per well) were seeded in 96-well plate. Calu-3suggested: None… SciScore for 10.1101/2022.03.08.483429: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication Authentication: The ff99+bsc0+χOL3 force field was used for MD simulation since this is the most validated and recommended FFs for RNA system (31). Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For experiments with the different SARS-CoV-2 variant and analogues of geneticin, Vero-E6 cells were overlaid instead with 0.4% avicel gp3515 in medium containing 2.5% FBS. Vero-E6suggested: NoneAntiviral assay in Calu3 cells: Calu-3 cells (4 x 104 cells per well) were seeded in 96-well plate. Calu-3suggested: NoneSoftware and Algorithms Sentences Resources The 50 % cytotoxic concentrations (CC50) and 95 % confidence intervals (CIs) were determined using Prism software (Graph-Pad Software, San Diego, CA). Prismsuggested: (PRISM, RRID:SCR_005375)EC50 was calculated with Prism 8 (GraphPad). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)The EC50 and CC50 values for inhibition curves were calculated by regression analysis using the program GraphPad Prism version 8.0 (GraphPad Software, California, USA) to fit a variable slope sigmoidal dose-response curve. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Molecular dynamic simulations: MD simulations were performed with Gromacs software package. Gromacssuggested: (GROMACS, RRID:SCR_014565)The Geneticin and the RNA-targeting compounds were prepared using the Maestro LigPrep tool by energy minimising the structures (OPLS4 force filed), generating possible ionisation states at pH 7 ± 2 (Epik), tautomers and stereoisomers per each ligand. Maestrosuggested: (Maestro, RRID:SCR_016748)LigPrepsuggested: (Ligprep, RRID:SCR_016746)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:The resulting antiviral activity is however linked to several limitations: the activity is in the micromolar range, and further studies should focus on the identification of more potent compounds. The antiviral activity is at nontoxic concentrations, also in human derived respiratory tissues (Supplementary Figure 2), however the selectivity index of geneticin is narrow since it is known to bind eukaryotic ribosome and it is associated with toxicity in cell culture. Although the administration in a viral infection is most likely to be for a short duration, future work should be directed to the identification of compounds devoid of interaction with ribosomal RNA. Moreover, aminoglycosides are associated with nephrotoxicity and ototoxicity when administered systemically, therefore a topical administration should be envisaged for compounds similar to geneticin. For these reasons, and to validate the druggability of the binding pocket identified, we used a virtual screening simulation to identify additional molecules, from a library of RNA binders. Our in silico screening against the “J2/3- stem 3” site revealed that the architecture of the pocket might be sufficiently complex to be targeted by more specific ligands. Through our simulations, we have identified molecules that might engage the FSE targeting the J2/3- stem 3 pocket, enhancing or reducing the pseudoknot stability. The identification of compound 3 with increased potency, reduction of RNA replication, and alteration of ...
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.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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