Furin cleavage of the SARS-CoV-2 spike is modulated by
            <i>O</i>
            -glycosylation

Zhang, Liping; Mann, Matthew; Syed, Zulfeqhar A.; Reynolds, Hayley M; Tian, E; Samara, N.L.; Zeldin, Darryl C.; Tabak, Lawrence A.; Hagen, Karl S.

doi:10.1073/pnas.2109905118

Cited by 119 publications

(91 citation statements)

References 20 publications

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“…The infectivity of SARS-CoV-2 is mainly determined by the binding affinity of the ACE2 and RBD complex, although the furin cleavage site plays a crucial role as well. 18 Omicron has three mutations at the furin cleavage site and 15 mutations on the RBD, suggesting a significant change in its infectivity. Due to natural selection, the virus enhances its evolutionary advantages at the RBD either by mutations to strengthen the ACE2-RBD binding affinity or by mutations to escape antibody protection.…”

Section: Resultsmentioning

confidence: 99%

Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

Chen

Wang

Gilby³

et al. 2022

J. Chem. Inf. Model.

612

587

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The latest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron (B.1.1.529) has ushered panic responses around the world due to its contagious and vaccine escape mutations. The essential infectivity and antibody resistance of the SARS-CoV-2 variant are determined by its mutations on the spike (S) protein receptor-binding domain (RBD). However, a complete experimental evaluation of Omicron might take weeks or even months. Here, we present a comprehensive quantitative analysis of Omicron’s infectivity, vaccine breakthrough, and antibody resistance. An artificial intelligence (AI) model, which has been trained with tens of thousands of experimental data and extensively validated by experimental results on SARS-CoV-2, reveals that Omicron may be over 10 times more contagious than the original virus or about 2.8 times as infectious as the Delta variant. On the basis of 185 three-dimensional (3D) structures of antibody–RBD complexes, we unveil that Omicron may have an 88% likelihood to escape current vaccines. The U.S. Food and Drug Administration (FDA)-approved monoclonal antibodies (mAbs) from Eli Lilly may be seriously compromised. Omicron may also diminish the efficacy of mAbs from AstraZeneca, Regeneron mAb cocktail, Celltrion, and Rockefeller University. However, its impacts on GlaxoSmithKline’s sotrovimab appear to be mild. Our work calls for new strategies to develop the next generation mutation-proof SARS-CoV-2 vaccines and antibodies.

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Section: Resultsmentioning

confidence: 99%

Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

Chen

Wang

Gilby³

et al. 2022

J. Chem. Inf. Model.

612

587

View full text Add to dashboard Cite

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“…These findings suggest enhanced binding of Delta spike protein to the ACE2 receptor, which may potentially contribute to greater infectivity and replication in ACE2-positive target cells. Since P681H enhanced proteolytic processing of B.1.1.7 spike [29,49], we next evaluated spike proteolytic processing of B.1.617 pseudovirus variants carrying the P681R substitution. The B.1.617 variant pseudoviruses displayed efficient proteolytic processing of spike compared to Wuhan-Hu-1 (D614) and WT(D614G) as observed by the S1/S ratio (Figure 5A).…”

Section: B1617 Pseudovirus Infectivity and Spike Protein Processingmentioning

confidence: 99%

SARS-CoV-2 Delta Variant Displays Moderate Resistance to Neutralizing Antibodies and Spike Protein Properties of Higher Soluble ACE2 Sensitivity, Enhanced Cleavage and Fusogenic Activity

Neerukonda

Vassell

Lusvarghi

et al. 2021

Viruses

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The SARS-CoV-2 B.1.617 lineage variants, Kappa (B.1.617.1) and Delta (B.1.617.2, AY) emerged during the second wave of infections in India, but the Delta variants have become dominant worldwide and continue to evolve. Here, we compared B.1.617 variants for neutralization resistance by convalescent sera, mRNA vaccine-elicited sera, and therapeutic neutralizing antibodies using a pseudovirus neutralization assay. B.1.617.1, B.1.617.2, and AY.1 pseudoviruses showed a modest 1.5- to 4.4-fold reduction in neutralization by convalescent sera and vaccine-elicited sera. In comparison, similar modest reductions were also observed for C.37, P.1, R.1, and B.1.526 pseudoviruses, but 7- and 16-fold reductions for vaccine-elicited and convalescent sera, respectively, were seen for B.1.351 pseudoviruses. Among twenty-three therapeutic antibodies tested, four antibodies showed either complete or partial loss of neutralization against B.1.617.2 pseudoviruses and six antibodies showed either complete or partial loss of neutralization against B.1.617.1 and AY.1 pseudoviruses. Our results indicate that the current mRNA-based vaccines will likely remain effective in protecting against B.1.617 variants. Finally, the P681R substitution confers efficient cleavage of B.1.617 variants’ spike proteins and the spike of Delta variants exhibited greater sensitivity to soluble ACE2 neutralization, as well as fusogenic activity, which may contribute to enhanced spread of Delta variants.

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“…4 Recent clinical data for the highly mutated Omicron variant has already been demonstrated to cause higher rates of reinfection and rampant breakthrough infections despite mRNA vaccine booster dose. 5 Furthermore, S protein glycosylation is critically involved in human receptor ACE2 binding, 6 cell infectivity, 7 and shields epitopes from antibody neutralization. 8 Although S protein N-glycosylation has been characterized in detail 9 with ongoing efforts to understand the impact of N-glycosylation for vaccine development, 10 characterization of O-glycosylation is challenging 11 due to the large microheterogeneity and structural diversity of O-glycans leading to multiple Oglycoforms.…”

Section: Introductionmentioning

confidence: 99%

Distinct Core Glycan and O-Glycoform Utilization of SARS-CoV-2 Omicron Variant Spike Protein RBD Revealed by Top-Down Mass Spectrometry

Roberts

Mann

et al. 2022

Preprint

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The SARS-CoV-2 Omicron (B.1.1.529) variant possesses numerous spike (S) mutations that enhance transmissibility and evasion of neutralizing antibodies, making it a serious threat to existing COVID-19 vaccines and therapies. Accurately distinguishing emerging S variants and revealing their post-translational glycosylation changes can provide new insights for rational design and development of vaccines and therapeutics. Here we report the first comprehensive elucidation of the molecular variations and O-glycoform changes of the Omicron, Delta (B.1.617.2), and wild-type (WA1/2020) S receptor-binding domains (S-RBDs) using high-resolution top-down mass spectrometry (MS). A novel O-glycosite (Thr376) unique to the Omicron variant is identified. Moreover, we have directly quantified the Core 1 and Core 2 O-glycan structures and characterized the O-glycoform structural heterogeneity of the three variants. Our findings provide high resolution detail of Omicron O-glycoform and utilization, providing new insights into how this variant escapes immunological protection and informing strategies for developing Omicron-directed vaccines, diagnostics, and therapeutics.

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Furin cleavage of the SARS-CoV-2 spike is modulated by O -glycosylation

Cited by 119 publications

References 20 publications

Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

SARS-CoV-2 Delta Variant Displays Moderate Resistance to Neutralizing Antibodies and Spike Protein Properties of Higher Soluble ACE2 Sensitivity, Enhanced Cleavage and Fusogenic Activity

Distinct Core Glycan and O-Glycoform Utilization of SARS-CoV-2 Omicron Variant Spike Protein RBD Revealed by Top-Down Mass Spectrometry

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