SARS-CoV-2 的分子流行病学：精氨酸在突变和传染性方面的主导作用。

Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity.

机构信息

Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne 8001, VIC, Australia.

AquaMem Consultants, Rodeo, NM 88056, USA.

出版信息

Viruses. 2023 Jan 22;15(2):309. doi: 10.3390/v15020309.

, , , , Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CL) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants' distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2' (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.

严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）因其能够突变为传播速度比野生型病毒更快的变体而成为全球性挑战。该病毒的分子生物学已得到广泛研究，应用的计算方法是新型抗病毒药物治疗的范例。SARS-CoV-2 在人群中的快速进化部分是由于刺突（S-）蛋白受体结合域（RBD）中的突变引起的，其中一些突变使病毒与血管紧张素转化酶（ACE2）的结合更加紧密。更稳定的 RBD-ACE2 结合与蛋白酶（如弗林蛋白酶、胰蛋白酶和跨膜丝氨酸蛋白酶 2（TMPRSS2））的加速水解有关，这些蛋白酶会增加感染率，而 3-糜蛋白酶样蛋白酶（3CL）的抑制可以阻止病毒复制。此外，非 RBD 和非界面突变可能有助于 S 蛋白采用热力学有利的构象以实现更强的结合。本研究旨在报告 across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across across the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2' (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.