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

Abstract

Background, Aims, Methods, Results, Conclusions: 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 (3CLpro) 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.

Network-Based Prediction of Side Effects of Repurposed Antihypertensive Sartans against COVID-19 via Proteome and Drug-Target Interactomes

“…Pioneering research on RAAS has resulted in the discovery of the first orally active ARB antagonist, Losartan (DUP753), followed by the development of a series of other potent Sartans for the treatment of hypertension [ 88 ]. Since ACE2, which is a part of RAAS and the entry point of SARs-CoV-2 in the cell, Sartans bearing anionic groups, tetrazolate, and carboxylate, were investigated as possible antivirals for the treatment of COVID-19, either by blocking entry or replication of the virus [ 13 , 22 , 23 ]. Extensive clinical studies have shown that ARBs are beneficial in the treatment of hypertensive patients infected by COVID-19 [ 89 , 90 ].…”

“… Chemical structures of BisA (4-Butyl-N,N0-bis{[[20-(2H-tetrazol-5-yl)]biphenyl-4-yl] methylimidazolium bromide), BisB (4-Butyl-2-hydroxymethyl-N,N0-bis{[20-(2H-tetrazol-5-yl)-biphenyl-4-yl]- methyimidazolium bromide), BisC (2-Butyl-4-chloro-5-hydroxymethyl-N,N0-bis{[20-(2Htetrazol-5-yl)biphenyl-4-yl]methylpimidazolium bromide) (Dialkylated losartan), BisD (2-Butyl-N,N0-bis{[20-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}x In imidazolium bromide). Note that the tetrazole group is deprotonated at physiological pH [ 13 , 22 , 23 ]. Illustrations were made with MarvinSketch, version 22.22.0 [ 24 ].…”

“… Chemical structures of Valsartan, Telmisartan, Olmesartan, Candesartan cilexetil, Irbesartan, Eprosartan, Losartan, Azilsartan medoxomil, Ritonavir, and Nirmatrelvir. Note that some of these may be deprotonated at physiological pH [ 13 , 22 , 23 ]. Illustrations were made with MarvinSketch, version 22.22.0 [ 24 ].…”

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics

“…Our research team discovered and synthesized a new cohort of antihypertensive drugs that were predicted to stably dock at catalytic site and semi-stably at furin-cleavage site (residues 681-686) of the transmembrane angiotensin-converting enzyme 2 (ACE2), which is the primary receptor for attachment and entry of SARS-CoV-2 into susceptible host tissues [19][20][21][22][23][24]. We refer to this new class of drugs as "bisartans" since they share structural similarities to the "sartan" therapeutics (e.g., Losartan, Olmesartan, Telmisartan, Irbersartan, Valsartan, etc.)…”

W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics

“…Because of this, “arginine blockers” (ARBs; e.g., Sartans) containing anionic tetrazole and/or carboxyl functional groups, and in particular Bisartans containing two tetrazole moieties with increased acidity, represent promising repurposed antiviral drugs [23] . Thus, drugs in the Sartan family can block furin activity (and subsequent infection) by obstructing basic amino acids of cleavage sites [24] , [25] , [26] . Clinical studies have shown the beneficial effect of ARBs Telmisartan, Candesartan, Losartan in hypertension patients infected by SARs-CoV-2 compared to patients not taking ARBs [27] , [28] .…”