Hossain Mohammad Uzzal, Bhattacharjee Arittra, Emon Md Tabassum Hossain, Chowdhury Zeshan Mahmud, Ahammad Ishtiaque, Mosaib Md Golam, Moniruzzaman Md, Rahman Md Hadisur, Islam Md Nazrul, Ahmed Irfan, Amin Md Ruhul, Rashed Asif, Das Keshob Chandra, Keya Chaman Ara, Salimullah Md
Bioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh.
Department of Biochemistry and Microbiology, North South University, Bashundhara, Dhaka, 1229, Bangladesh.
J Genet Eng Biotechnol. 2021 Apr 2;19(1):52. doi: 10.1186/s43141-021-00152-z.
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.
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.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是2019冠状病毒病（COVID-19）的病原体，正在迅速获得新的突变。对这些突变进行分析对于了解治疗开发的不同方面至关重要。此前，我们报道了一种基于桑格法的、在孟加拉国传播的名为SARS-CoV-2 NIB-1的病毒分离株的基因组序列。该基因组在V121D、V843F、A889V和G1691C位置有四个新的非同义突变。
使用不同的计算工具，我们发现V121D替换有可能使非结构蛋白-1（NSP-1）不稳定。NSP-1可使1型干扰素诱导的抗病毒系统失活。因此，这种突变体可能是抗SARS-CoV-2减毒疫苗的基础。V843F、A889V和G1691C均位于非结构蛋白-3（NSP-3）中。G1691C可降低蛋白质的灵活性。V843F和A889V可能会改变SARS-CoV-2木瓜样蛋白酶（PLPro）抑制剂GRL0617的结合模式和效力。PLPro中的V843F替换是临床样本中最常见的突变。这种突变对干扰素刺激基因-15蛋白（ISG-15）的亲和力降低，可能会影响先天免疫和病毒传播。然而，V843F+A889V双突变体表现出与野生型PLPro相同的结合亲和力。这种现象背后的一个可能原因是，V843F是PLPro的一个保守残基，它破坏了蛋白酶结构，但A889V是一个保守性较低的残基，大概中和了这种破坏。
NSP-1的突变体可为冠状病毒提供减毒疫苗。此外，PLPro的这些突变可能是开发更好的抗SARS治疗药物的靶点。我们希望我们的研究将有助于在减毒疫苗和PLPro抑制剂的开发过程中获得更好的见解。
