J Genet Eng Biotechnol . Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics

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J Genet Eng Biotechnol


. 2021 Apr 2;19(1):52.
doi: 10.1186/s43141-021-00152-z.
Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics


Mohammad Uzzal Hossain ^{# 1} , Arittra Bhattacharjee ^{# 1 2} , Md Tabassum Hossain Emon ^{# 3} , Zeshan Mahmud Chowdhury ² , Ishtiaque Ahammad ¹ , Md Golam Mosaib ⁴ , Md Moniruzzaman ⁵ , Md Hadisur Rahman ⁵ , Md Nazrul Islam ⁶ , Irfan Ahmed ⁵ , Md Ruhul Amin ⁷ , Asif Rashed ⁸ , Keshob Chandra Das ⁵ , Chaman Ara Keya ² , Md Salimullah ⁹



Affiliations

• PMID: 33797663
• DOI: 10.1186/s43141-021-00152-z

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.

Keywords: COVID-19; GRL0617; ISG-15; NSP-1; Papain-like protease; SARS-CoV-2.