Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics
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Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease-2019 (COVID-19), is rapidly accumulating new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Recently, we have reported a Sanger method based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel mutations in V121D, V843F, A889V and G1691C positions. V121D substitution has the potential to destabilize the Non-Structural Protein (NSP-1) which inactivates the type-1 Interferon-induced antiviral system hence this mutant could be the basis of attenuated vaccines against SARS-CoV-V843F, A889V and G1691C are all located in NSP3. G1691C can decrease the flexibility of the protein while V843F and A889V changed the binding pattern of SARS-CoV-2 Papain-Like protease (PLPro) inhibitor GRL0617. V843F PLPro showed reduced affinity for Interferon Stimulating Gene-15 (ISG-15) protein whereas V843F+A889V double mutants exhibited the same binding affinity as wild type PLPro. Here, V843F is a conserved position of PLPro that damaged the structure but A889V, a less conserved residue, most probably neutralized that damage. Mutants of NSP1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro could be targeted to develop anti-SARS therapeutics.
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SciScore for 10.1101/2020.12.02.408229: (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
Software and Algorithms Sentences Resources The genome was aligned with the reference genome by NCBI Nucleotide Basic Local Alignment Search Tools (BLASTN) to identify the mutations in the Untranslated Regions (UTRs) [16]. BLASTNsuggested: (BLASTN, RRID:SCR_001598)To assess the effect of the novel mutations, MUpro, Protein Variation Effect Analyzer (PROVEAN) and HOPE were employed [19–21]. PROVEANsuggested: (PROVEAN, RRID:SCR_002182)The generated structures were energetically minimized by 3D Refine and then again refined by Galaxy Refine [24, 25]. 2.4. Galaxysuggested: (Galaxy, RRID:SCR_006281)1-naphthyl) ethyl] benzamide (PubChem … SciScore for 10.1101/2020.12.02.408229: (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
Software and Algorithms Sentences Resources The genome was aligned with the reference genome by NCBI Nucleotide Basic Local Alignment Search Tools (BLASTN) to identify the mutations in the Untranslated Regions (UTRs) [16]. BLASTNsuggested: (BLASTN, RRID:SCR_001598)To assess the effect of the novel mutations, MUpro, Protein Variation Effect Analyzer (PROVEAN) and HOPE were employed [19–21]. PROVEANsuggested: (PROVEAN, RRID:SCR_002182)The generated structures were energetically minimized by 3D Refine and then again refined by Galaxy Refine [24, 25]. 2.4. Galaxysuggested: (Galaxy, RRID:SCR_006281)1-naphthyl) ethyl] benzamide (PubChem CID: 24941262) is a PLPro inhibitor with a relatively low level of cytotoxicity [27]. PubChemsuggested: (PubChem, RRID:SCR_004284)Here, we analyzed the interactions between GRL0617 and PLPro by AutoDock Vina using our previously reported methodology for exploring drug-receptor interactions [28, 29]. AutoDocksuggested: (AutoDock, RRID:SCR_012746), BIOVIA Discovery Studio and PyMOL Molecular Graphics System, Version 2.3.3 Schrödinger, LLC. 2.6. Analysis of ISG15-PLPro interactions: ISG15 C-terminal domain that interacts with PLPro was collected from PDB ID: 6XA9. PyMOLsuggested: (PyMOL, RRID:SCR_000305)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: Please consider improving the rainbow (“jet”) colormap(s) used on page 21. 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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