SARS-CoV-2 RBD <i>in vitro</i> evolution follows contagious mutation spread, yet generates an able infection inhibitor

Zahradník, Jiří; Marciano, Shir; Shemesh, Maya; Zoler, Eyal; Chiaravalli, Jeanne; Meyer, Björn; Rudich, Yinon; Dym, Orly; Elad, Nadav; Schreiber, Gideon

doi:10.1101/2021.01.06.425392

Cited by 125 publications

(135 citation statements)

References 47 publications

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“…Therefore, the escape of mAb48 neutralization by the two variants is due to mutations decreasing or abrogating antibody binding to its target. The N501Y mutation enhances RBD affinity to ACE2, when tested with recombinant proteins and yeast surface display 20 . We assessed by flow cytometry the binding of a labelled soluble ACE2 protein to cells expressing the different Spikes.…”

Section: Antibody Binding To Cells Expressing D614g B117 and B1mentioning

confidence: 99%

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Planas

Bruel

Grzelak

et al. 2021

Preprint

272

368

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SARS-CoV-2 B.1.1.7 and B.1.351 variants emerged respectively in United Kingdom and South Africa and spread in many countries. Here, we isolated infectious B.1.1.7 and B.1.351 strains and examined their sensitivity to anti-SARS-CoV-2 antibodies present in sera and nasal swabs, in comparison with a D614G reference virus. We established a novel rapid neutralization assay, based on reporter cells that become GFP+ after overnight infection. B.1.1.7 was neutralized by 79/83 sera from convalescent patients collected up to 9 months post symptoms, almost similar to D614G. There was a mean 6-fold reduction in titers and even loss of activity against B.1.351 in 40% of convalescent sera after 9 months. Early sera from 19 vaccinated individuals were almost as potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Nasal swabs from vaccine recipients were not neutralizing, except in individuals who were diagnosed COVID-19+ before vaccination. Thus, faster-spreading variants acquired a partial resistance to humoral immunity generated by natural infection or vaccination, mostly visible in individuals with low antibody levels.

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Section: Antibody Binding To Cells Expressing D614g B117 and B1mentioning

confidence: 99%

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Planas

Bruel

Grzelak

et al. 2021

Preprint

272

368

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“…Of great interest are variants that include mutations with the potential to affect the interaction of the SARS-CoV-2 spike receptor binding domain (S RBD) with the host receptor, angiotensinconverting enzyme 2 (ACE2). The binding of the S RBD of SARS-CoV-2, like SARS-CoV before it, to ACE2 initiates infection [4][5][6][7] , thus variants that have a greater binding affinity for ACE2 are likely to be more readily transmissible 8 . Transmissibility goes hand-in-hand with mortality, because even if a variant does not produce a higher rate of morbidity or mortality, the total number of severe cases and death would be expected to increase due to what may be an exponential increase in infections.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant

Nelson

Buzko

Spilman

et al. 2021

Preprint

202

220

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Rapidly spreading SARS-CoV-2 variants present not only an increased threat to human health due to the confirmed greater transmissibility of several of these new strains but, due to conformational changes induced by the mutations, may render first-wave SARS-CoV-2 convalescent sera, vaccine-induced antibodies, or recombinant neutralizing antibodies (nAbs) ineffective. To be able to assess the risk of viral escape from neutralization by first-wave antibodies, we leveraged our capability for Molecular Dynamic (MD) simulation of the spike receptor binding domain (S RBD) and its binding to human angiotensin-converting enzyme 2 (hACE2) to predict alterations in molecular interactions resulting from the presence of the E484K, K417N, and N501Y variants found in the South African 501Y.V2 strain – alone and in combination. We report here the combination of E484K, K417N and N501Y results in the highest degree of conformational alterations of S RBD when bound to hACE2, compared to either E484K or N501Y alone. Both E484K and N501Y increase affinity of S RBD for hACE2 and E484K in particular switches the charge on the flexible loop region of RBD which leads to the formation of novel favorable contacts. Enhanced affinity of S RBD for hACE2 very likely underpins the greater transmissibility conferred by the presence of either E484K or N501Y; while the induction of conformational changes may provide an explanation for evidence that the 501Y.V2 variant, distinguished from the B.1.1.7 UK variant by the presence of E484K, is able to escape neutralization by existing first-wave anti-SARS-CoV-2 antibodies and re-infect COVID-19 convalescent individuals.

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“…The 501Y.V1 strain carries the N501Y mutation in the RBM of the S protein. Experimental and simulation studies have revealed that the N501Y mutation improves the binding affinity of RBD to the receptor hACE2, which is believed to account for the more transmissibility of the 501Y.V1 variant than the original strains [28][29][30][31][32]. Fortunately, the sera neutralization assay showed that the N501Y mutation has little effect on the neutralization of the human sera elicited by the BNT162b2 mRNA vaccine [25].…”

Section: Introductionmentioning

confidence: 99%

E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

Wang

Liang

Jin

et al. 2021

Preprint

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The pandemic of the COVID-19 disease caused by SARS-CoV-2 has led to more than 100 million infections and over 2 million deaths worldwide. The progress in the developments of effective vaccines and neutralizing antibody therapeutics brings hopes to eliminate the threat of COVID-19. However, SARS-CoV-2 continues to mutate, and several new variants have been emerged. Among the various naturally-occurring mutations, the E484K mutation shared by both the 501Y.V2 and 501Y.V3 variants attracted serious concerns, which may potentially enhance the receptor binding affinity and reduce the immune response. In the present study, the molecular mechanism behind the impacts of E484K mutation on the binding affinity of the receptor-binding domain (RBD) with the receptor human angiotensin-converting enzyme 2 (hACE2) was investigated by using the molecular dynamics (MD) simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method. Our results indicate that the E484K mutation results in more favorable electrostatic interactions compensating the burial of the charged and polar groups upon the binding of RBD with hACE2, which significantly improves the RBD-hACE2 binding affinity. Besides that, the E484K mutation also causes the conformational rearrangements of the loop region containing the mutant residue, which leads to more tight binding interface of RBD with hACE2 and formation of some new hydrogen bonds. The more tight binding interface and the new hydrogen bonds formation also contribute to the improved binding affinity of RBD to the receptor hACE2. In addition, six neutralizing antibodies and nanobodies complexed with RBD were selected to explore the effects of E484K mutation on the recognition of these antibodies to RBD. The simulation results show that the E484K mutation significantly reduces the binding affinities to RBD for most of the studied neutralizing antibodies, and the decrease in the binding affinities is mainly owing to the unfavorable electrostatic interactions caused by the mutation. Our studies revealed that the E484K mutation may improve the binding affinity between RBD and the receptor hACE2, implying more transmissibility of the E484K-containing variants, and weaken the binding affinities between RBD and the studied neutralizing antibodies, indicating reduced effectiveness of these antibodies. Our results provide valuable information for the effective vaccine development and antibody drugs design.

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SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor

Cited by 125 publications

References 47 publications

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant

E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

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