Acquisition of the L452R Mutation in the ACE2-Binding Interface of Spike Protein Triggers Recent Massive Expansion of SARS-CoV-2 Variants

Tchesnokova, Veronika; Kulasekara, Hemantha D.; Larson, Lydia; Bowers, Victoria; Rechkina, Elena; Kisiela, Dagmara I.; Sledneva, Yulia; Choudhury, Devapriya; Maslova, Iryna; Deng, Kai; Kutumbaka, Kirthi K.; Geng, Hao; Fowler, Curtis; Greene, Dina N.; Ralston, James D.; Samadpour, Mansour; Sokurenko, Evgeni V.

doi:10.1128/jcm.00921-21

Cited by 152 publications

(98 citation statements)

References 20 publications

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“…The alpha, gamma, delta and kappa variants of SARS-CoV-2 have N501Y, N501Y plus E484K, L452R, L452R plus E484Q mutations, respectively, in the viral Spike proteins [8][9][10]20,21]. These amino acid substitutions may be associated with the high contagiousness and/or immune escape of the variants [20,21]. We previously showed that TFDG may bind to the receptor binding domain (RBD) of the Spike proteins [7].…”

Section: Discussionmentioning

confidence: 99%

Milk casein prevents inactivation effect of black tea galloylated theaflavins on SARS-CoV-2 in vitro

Ohgitani

Shin‐Ya

Ichitani³

et al. 2021

Preprint

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Repeated emergence of highly contagious and potentially immune-evading variant SARS-CoV-2 is posing global health and socioeconomical threats. For suppression of the spread of the virus infection among people, a procedure to inactivate virus in saliva may be useful, because saliva of infected persons is the major origin of droplets and aerosols that mediate viral transmission to nearby persons. We previously reported that SARS-CoV-2 is rapidly and remarkably inactivated by treatment in vitro with tea including green tea, roasted green tea, oolong tea and black tea. Tea catechin-derived compounds including theaflavins (TFs) with (a) galloyl moiety(ies) showed this activity. Although black tea is popularly consumed worldwide, a lot of people consume it with sugar, milk, lemon juice, and so on. But it has not been determined whether these ingredients may influence the inactivation effect of black tea against SARS-CoV-2. Moreover, it has not been revealed whether black tea is capable of inactivating variant viruses such as delta variant. Here we examined the effect of black tea on some variants in the presence or absence of sugar, milk, and lemon juice in vitro. Black tea and galloylated TFs remarkably inactivated alpha, gamma, delta and kappa variants. Intriguingly, an addition of milk but not sugar and lemon juice totally prevented black tea from inactivating alpha and delta variant viruses. The suppressive effect was also exerted by milk casein. These results suggest the possibility that intake of black tea without milk by infected persons may result in inactivation of the virus in saliva and attenuation of spread of SARS-CoV-2 to nearby persons through droplets. Clinical studies are required to investigate this possibility.

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Section: Discussionmentioning

confidence: 99%

Milk casein prevents inactivation effect of black tea galloylated theaflavins on SARS-CoV-2 in vitro

Ohgitani

Shin‐Ya

Ichitani³

et al. 2021

Preprint

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“…The fact that some mutations have been acquired by different independent lineages in separate countries suggests there is a strong positive selection and possibly reflects an adaptive evolution of the virus in response to either the epidemiological control measures or a growing immunity to the original viral variants. Positive selection could therefore favor increased transmissibility, infectivity and/or immune escape of the virus [29].…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study between Spanish and British SARS-CoV-2 Variants

Ruiz

Ramírez

Lόpez-Campos

2021

CIMB

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The study of the interaction between the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor is key to understanding binding affinity and stability. In the present report, we sought to investigate the differences between two already sequenced genome variants (Spanish and British) of SARS-CoV-2. Methods: In silico model evaluating the homology, identity and similarity in the genome sequence and the structure and alignment of the predictive spike by computational docking methods. Results: The identity results between the Spanish and British variants of the Spike protein were 28.67%. This close correspondence in the results between the Spanish and British SARS-CoV-2 variants shows that they are very similar (99.99%). The alignment obtained results in four deletions. There were 23 nucleotide substitutions also predicted which could affect the functionality of the proteins produced from this sequence. The interaction between the binding receptor domain from the spike protein and the ACE2 receptor produces some of the mutations found and, therefore, the energy of this ligand varies. However, the estimated antigenicity of the British variant is higher than its Spanish counterpart. Conclusions: Our results indicate that minimal mutations could interfere in the infectivity of the virus due to changes in the fitness between host cell recognition and interaction proteins. In particular, the N501Y substitution, situated in the RBD of the spike of the British variant, might be the reason for its extraordinary infective potential.

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“…Residue L452 is positioned at the edge of the binding interface with ACE2 and although this residue does not make direct contact with ACE2 [34,77], evidence suggests that substitution L452R enhances viral infectivity significantly [77,78]. Furthermore, it has been suggested that the L452R mutation is responsible for the dramatic clonal expansion of lineages carrying this mutation [79], possibly due to a decrease in the potency of antibody neutralization or through other immune escape characteristics [44,46,64,77,78,80]. Whether or not an effect of the L452R substitution on ACE2 binding, apparently modest, is a contributing factor in the rapid spread of variants carrying this mutation remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A bacteria-based assay to study SARS-CoV-2 protein-protein interactions

Hochschild

Springstein

Deighan

et al. 2021

Preprint

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Methods for detecting and dissecting the interactions of virally encoded proteins are essential for probing basic viral biology and providing a foundation for therapeutic advances. The dearth of targeted therapeutics for the treatment of COVID-19, an ongoing global health crisis, underscores the importance of gaining a deeper understanding of the interactions of SARS-CoV-2-encoded proteins. Here we describe the use of a convenient bacteria-based two-hybrid (B2H) system to analyze the SARS-CoV-2 proteome. We identify sixteen distinct intraviral protein-protein interactions (PPIs), involving sixteen proteins. We find that many of the identified proteins interact with more than one partner. We further show how our system facilitates the genetic dissection of these interactions, enabling the identification of selectively disruptive mutations. We also describe a modified B2H system that permits the detection of disulfide bond-dependent PPIs in the normally reducing Escherichia coli cytoplasm and we use this system to detect the interaction of the SARS-CoV-2 spike protein receptor-binding domain (RBD) with its cognate cell surface receptor ACE2. We then examine how the RBD-ACE2 interaction is perturbed by several RBD amino acid substitutions found in currently circulating SARS-CoV-2 variants. Our findings illustrate the utility of a genetically tractable bacterial system for probing the interactions of viral proteins and investigating the effects of emerging mutations. In principle, the system could also facilitate the identification of potential therapeutics that disrupt specific interactions of virally encoded proteins. More generally, our findings establish the feasibility of using a B2H system to detect and dissect disulfide bond-dependent interactions of eukaryotic proteins.

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Acquisition of the L452R Mutation in the ACE2-Binding Interface of Spike Protein Triggers Recent Massive Expansion of SARS-CoV-2 Variants

Cited by 152 publications

References 20 publications

Milk casein prevents inactivation effect of black tea galloylated theaflavins on SARS-CoV-2 in vitro

Milk casein prevents inactivation effect of black tea galloylated theaflavins on SARS-CoV-2 in vitro

A Comparative Study between Spanish and British SARS-CoV-2 Variants

A bacteria-based assay to study SARS-CoV-2 protein-protein interactions

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