Emerging Dominant SARS-CoV-2 Variants

Chen, Jiahui; Wang, Rui; Hozumi, Yuta; Liu, Gengzhuo; Qiu, Yuchi; Wei, Xiaoqi; Wei, Guo-Wei

doi:10.1021/acs.jcim.2c01352

Cited by 21 publications

(23 citation statements)

References 41 publications

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“…The five dominant VOCs that have been reported so far (as of November 2022) are alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529) ([ 35 ], accessed on 24 November 2022). The first two variants (i.e., alpha and beta) were responsible for the peak of COVID-19 infections and deaths from October 2020 to the beginning of summer 2021 (depending on the area), while the third variant (i.e., gamma) was mainly circulated during the same period in Brazil and L. America [ 36 ]. The third wave of COVID-19 was caused by the fourth variant, named delta, which circulated from April 2021 until the end of the year.…”

Section: Resultsmentioning

confidence: 99%

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

Ridgway

Ntallis

Chasapis

et al. 2023

Viruses

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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.

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Section: Resultsmentioning

confidence: 99%

“…BQ.1.1 is another sublineage of the original BA.5 variant and exhibits high potential to replace BA.5 and become the new dominant variant. Based on modeling estimates, by the beginning of 2023, more than 80% of COVID-19 cases are expected to be due to BQ.1/BQ.1.1 SARS-CoV-2 variants [ 18 , 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

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

Ridgway

Ntallis

Chasapis

et al. 2023

Viruses

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“…This would proficiently help develop rational predictive models of the effect of future variants and even design possible new antigens for vaccine update. Work in this direction has been carried out using extensive sequence information and ML to predict new evolutionary variants. − …”

Section: Discussionmentioning

confidence: 99%

Conformational Behavior of SARS-Cov-2 Spike Protein Variants: Evolutionary Jumps in Sequence Reverberate in Structural Dynamic Differences

Triveri

Casali

Frasnetti

et al. 2023

J. Chem. Theory Comput.

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SARS-CoV-2 has evolved rapidly in the first 3 years of pandemic diffusion. The initial evolution of the virus appeared to proceed through big jumps in sequence changes rather than through the stepwise accumulation of point mutations on already established variants. Here, we examine whether this nonlinear mutational process reverberates in variations of the conformational dynamics of the SARS-CoV-2 Spike protein (S-protein), the first point of contact between the virus and the human host. We run extensive microsecond-scale molecular dynamics simulations of seven distinct variants of the protein in their fully glycosylated state and set out to elucidate possible links between the mutational spectrum of the S-protein and the structural dynamics of the respective variant, at global and local levels. The results reveal that mutation-dependent structural and dynamic modulations mostly consist of increased coordinated motions in variants that acquire stability and in an increased internal flexibility in variants that are less stable. Importantly, a limited number of functionally important substructures (the receptor binding domain, in particular) share the same time of movements in all variants, indicating efficient preorganization for functional regions dedicated to host interactions. Our results support a model in which the internal dynamics of the S-proteins from different strains varies in a way that reflects the observed random and non-stepwise jumps in sequence evolution, while conserving the functionally oriented traits of conformational dynamics necessary to support productive interactions with host receptors.

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“…The biggest challenge with respect to managing the burden of COVID-19 is the continuous evolution of SARS-CoV-2 [16]. In particular, the emergence of the Omicron variants of the virus has significantly changed the landscape, and whereas previously there had been a sequential emergence of single predominant variants, we are now in the era of a pool of codominant variants [17, 18]. As of January 2023, the most recent Omicron subvariants of concern include XBB.1.5, BQ.1, and BQ.1.1 [19], and it has been shown that some monoclonal antibodies, including bebtelovimab, tixagevimab/cilgavimab, and casirivimab, lose their ability to neutralize these subvariants in vitro [20].…”

Section: Introductionmentioning

confidence: 99%

Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial

Moya

Temech

Parra

et al. 2023

Preprint

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Background: 500 mg intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary endpoint was occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through Day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through Day 29 were assessed. Results: All participants (n=81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through Day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n=2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on Day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 μg/mL. Viral load decreased from baseline through Day 29; only 2 participants (3%) had persistently high viral load (≥4.1 log10 copies/mL) at Day 8. Conclusions: 2000 mg IV sotrovimab was well tolerated, with no new unanticipated safety signals observed.

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Emerging Dominant SARS-CoV-2 Variants

Cited by 21 publications

References 41 publications

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

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

Conformational Behavior of SARS-Cov-2 Spike Protein Variants: Evolutionary Jumps in Sequence Reverberate in Structural Dynamic Differences

Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial

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