Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies

Zhu, Xing; Mannar, Dhiraj; Srivastava, Shanti Swaroop; Berezuk, Alison; Demers, Jean‐Philippe; Saville, James W.; Leopold, Karoline; Li, Wei; Dimitrov, Dimiter S.; Tuttle, K.S.; Zhou, Shaoyu; Chittori, Sagar; Subramaniam, Sriram

doi:10.1371/journal.pbio.3001237

Cited by 175 publications

(134 citation statements)

References 43 publications

(65 reference statements)

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“…For example, the RBD-targeting nAbs 2-15 and C121 exhibit a complete loss of neutralizing activity against the P.1 variant [ 121 ]. Neutralization of the B.1.1.7 variant by the RBD-targeting nAbs COVA2-15, COVA1-18, and S309 has also been found to be reduced, which might be potentially due to the N501Y mutation [ 119 ]; nevertheless, this mutation has minimal effect on the neutralizing activity of the nAbs IgG ab1 and V H -Fc ab8 [ 122 ]. In contrast to RBD-specific nAb ab6, which can neutralize a pseudotyped SARS-CoV-2 variant containing a triple mutation (K417N, E484K, N501Y), the nAbs COV2-2196, COV2-3025, COV2-2381, and S2E12 exhibit reduced neutralizing ability against the B.1.351 variant containing the E484K and N501Y mutations [ 117 , 123 ].…”

Section: Antigenic View Of the Ntd And Rbd Of Sars-cov-2 S Protein And Nab Binding Sitesmentioning

confidence: 99%

Neutralizing antibodies for the prevention and treatment of COVID-19

2021

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus–cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.

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Section: Antigenic View Of the Ntd And Rbd Of Sars-cov-2 S Protein And Nab Binding Sitesmentioning

confidence: 99%

Neutralizing antibodies for the prevention and treatment of COVID-19

2021

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“…The earliest variant to emerge and rapidly became dominant worldwide carried a D614G substitution and although studies suggested increased transmissibility ( 27 – 29 ), this variant was neutralized with existing monoclonal antibodies and convalescent sera ( 30 – 32 ). The emergence of the N501Y substitution was particularly concerning, which has been reported to be more transmissible than wild type and the D614G substitution ( 11 , 33 , 34 ). The N501Y substitution was first seen in the B.1.1.7 variant ( 23 ) and subsequently in the B.1351 ( 24 ) and P1 variants ( 35 ).…”

Section: Introductionmentioning

confidence: 99%

Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants

2021

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have become a major concern in the containment of current pandemic. The variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta) have shown reduced sensitivity to monoclonal antibodies, plasma and/or sera obtained from convalescent patients and vaccinated individuals. Development of potent therapeutic monoclonal antibodies (mAbs) with broad neutralizing breadth have become a priority for alleviating the devastating effects of this pandemic. Here, we review some of the most promising broadly neutralizing antibodies obtained from plasma of patients that recovered from early variants of SARS-CoV-2 that may be effective against emerging new variants of the virus. This review summarizes several mAbs, that have been discovered to cross-neutralize across Sarbecoviruses and SARS-CoV-2 escape mutants. Understanding the characteristics that confer this broad and cross-neutralization functions of these mAbs would inform on the development of therapeutic antibodies and guide the discovery of second-generation vaccines.

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“…N501 interacts with several residues of hACE2 including forming a hydrogen bond with Y41 of hACE2 to stabilize the virus-binding hotspot K353 at the RBD-hACE2 interface 3 . The N501Y mutation results in insertion of the aromatic ring of Y501 into a cavity between Y41 and K353 of hACE2, which increases RBD binding affinity to hACE2 11 . This ultimately leads to greater virus transmissibility, as the B.1.1.7 lineage is reportedly 43-90% more transmissible in the UK and 40-50% more transmissible in the US than early SARS-CoV-2 strains 8,12 .…”

Section: Introductionmentioning

confidence: 99%

B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

Radvák

Kwon

Košíková

et al. 2021

Preprint

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SARS-CoV-2 continues to circulate globally resulting in emergence of several variants of concern (VOC), including B.1.1.7 and B.1.351 that show increased transmissibility and enhanced resistance to antibody neutralization. In a K18-hACE2 transgenic mouse model, we demonstrate that Both B.1.1.7 and B.1.351 are 100 times more lethal than the original SARS-CoV-2 bearing 614D. Mice infected with B.1.1.7 and B.1.351 exhibited more severe lesions in internal organs than those infected with early SARS-CoV-2 strains bearing 614D or 614G. Infection of B.1.1.7 and B.1.351 also results in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death as compared to the mice infected with early SARS-CoV-2 strains. However, K18-hACE2 mice with the pre-existing immunity from prior infection or immunization were resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC. Our study reveals distinguishing pathogenic patterns of B.1.1.7 and B.1.351 variants from those early SARS-CoV-2 strains in K18-hACE2 mice, which will help to inform potential medical interventions for combating COVID-19.

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Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies

Cited by 175 publications

References 43 publications

Neutralizing antibodies for the prevention and treatment of COVID-19

Neutralizing antibodies for the prevention and treatment of COVID-19

Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants

B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

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