Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics

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-2. 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.

Emerging Mutations in Nsp1 of SARS-CoV-2 and Their Effect on the Structural Stability

“…Recently, four novel mutations have been detected in the genome of SARS-CoV2, among which V121D substitution exhibited a destabilizing effect on Nsp1 [ 49 ]. Similar to this study, we detected 18 non-synonymous mutations at positions aa 121 to 124, where all variants exhibited a destabilizing effect, except for V121I, V121W, and L122I.…”