Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics

Abstract

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is rapidly acquiring new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Previously, 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 non-synonymous mutations in V121D, V843F, A889V, and G1691C positions. Results Using different computational tools, we have found V121D substitution has the potential to destabilize the non-structural protein-1 (NSP-1). NSP-1 inactivates the type-1 interferon-induced antiviral system. Hence, this mutant could be a basis of attenuated vaccines against SARS-CoV-2. V843F, A889V, and G1691C are all located in nonstructural protein-3 (NSP-3). G1691C can decrease the flexibility of the protein. V843F and A889V might change the binding pattern and efficacy of SARS-CoV-2 papain-like protease (PLPro) inhibitor GRL0617. V843F substitution in PLPro was the most prevalent mutation in the clinical samples. This mutation showed a reduced affinity for interferon-stimulated gene-15 protein (ISG-15) and might have an impact on innate immunity and viral spread. However, V843F+A889V double mutant exhibited the same binding affinity as wild type PLPro. A possible reason behind this phenomenon can be that V843F is a conserved residue of PLPro which damaged the protease structure, but A889V, a less conserved residue, presumably neutralized that damage. Conclusions Mutants of NSP-1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro might be targeted to develop better anti-SARS therapeutics. We hope our study will help to get better insides during the development of attenuated vaccine and PLPro inhibitors.

HERC5 and the ISGylation Pathway: Critical Modulators of the Antiviral Immune Response

“…Knockdown of either ISG15 or MDA5 resulted in loss of IRF3 phosphorylation, which is a downstream target of MDA5 [104]. Fascinatingly, researchers have noted that naturally emerging mutations causing residue substitutions in the ISG15-binding pocket of PL pro results in less pathogenic strains of SARS-CoV-2 [144]. Thus far, the primary role of PL pro deISGylation appears to be suppression of the immune response, with more studies needed to determine if SARS-CoV-2 proteins are directly ISGylated by host cell machinery and if this has an overall inhibitory effect on the virus.…”

Emerging SARS-CoV-2 Variants: A Review of Its Mutations, Its Implications and Vaccine Efficacy

“…NSP1: The major functions of NSP1 include viral replication and inactivation of the type-1 interferon-induced antiviral system [ 36 ]. One important mutation, the deletion of three amino acids (KSF) at the AA position 241–243, has been shown to affect the structure of the C-terminal region of the protein, which is important for the regulation of viral replication and negative effect on the host’s gene expression [ 37 ].…”

Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants

“…Different nsps have their structures and functions, which can be changed by the mutations [186] . For example, the V121D mutation in nsp1 may have a disruptive effect on it, and the G1691C in Nsp3 reduces the flexibility of the protein [187] . Therefore, these mutations in nsps should be taken into account in drug and vaccine development or treatment against COVID-19.…”