scholarly journals Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

2020 ◽  
Author(s):  
Renhong Yan ◽  
Ruoke Wang ◽  
Bin Ju ◽  
Jinfang Yu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Intervention ◽  
Structural Features ◽  
Full Length ◽  
Structural Basis ◽  
Virus Infections ◽  
Virus Diseases ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Potent Neutralization

AbstractNeutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

scholarly journals Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Cell Research ◽  
2021 ◽  
Author(s):  
Renhong Yan ◽  
Ruoke Wang ◽  
Bin Ju ◽  
Jinfang Yu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Intervention ◽  
Structural Features ◽  
Full Length ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Neutralizing Activity ◽  
Potent Neutralization

AbstractNeutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.

scholarly journals Evolution of ACE2 and SARS-CoV-2 Interplay Across 247 Vertebrates

2021 ◽  
Author(s):  
Tao Zhang ◽  
Qunfu Wu ◽  
Yicheng Ma ◽  
Wenjing Liu ◽  
Chengang Zhou ◽  
...  
Keyword(s):  
Acid Sites ◽  
Rapid Expansion ◽  
Structural Basis ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Evolutionary Pattern ◽  
High Affinity ◽  
Treatment And Prevention ◽  
Infection Models ◽  
Potential Benefits

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause the most serious pandemics of Coronavirus Disease 2019 (COVID-19), which threatens human health and public safety. SARS-CoV-2 spike (S) protein uses angiotensin-converting enzyme 2 (ACE2) as recognized receptor for its entry into host cell that contributes to the infection of SARS-CoV-2 to hosts. Using computational modeling approach, this study resolved the evolutionary pattern of bonding affinity of ACE2 in 247 jawed vertebrates to the spike (S) protein of SARS-CoV-2. First, high-or-low binding affinity phenotype divergence of ACE2 to the S protein of SARS-CoV-2 has appeared in two ancient species of jawed vertebrates, Scyliorhinus torazame (low-affinity, Chondrichthyes) and Latimeria chalumnae (high-affinity, Coelacanthimorpha). Second, multiple independent affinity divergence events recur in fishes, amphibians-reptiles, birds, and mammals. Third, high affinity phenotypes go up in mammals, possibly implying the rapid expansion of mammals might accelerate the evolution of coronaviruses. Fourth, we found natural mutations at eight amino acid sites of ACE2 can determine most of phenotype divergences of bonding affinity in 247 vertebrates and resolved their related structural basis. Moreover, we also identified high-affinity or low-affinity-associated concomitant mutation group.The group linked to extremely high affinity may provide novel potentials for the development of human recombinant soluble ACE2 (hrsACE2) in treating patients with COVID-19 or for constructing genetically modified SARS-CoV-2 infection models promoting vaccines studies. These findings would offer potential benefits for the treatment and prevention of SARS-CoV-2.

scholarly journals Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants

Science ◽  
2021 ◽  
pp. eabi9745
Author(s):  
Yongfei Cai ◽  
Jun Zhang ◽  
Tianshu Xiao ◽  
Christy L. Lavine ◽  
Shaun Rawson ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Viral Fitness ◽  
Structural Basis ◽  
Amino Acid Substitutions ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Antigenic Properties ◽  
Structural Details ◽  
Fast Spreading

Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains in the COVID-19 pandemic. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Amino acid substitutions in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2). The enhanced receptor engagement may account for the increased transmissibility. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein, making it resistant to some potent neutralizing antibodies. These findings provide structural details on how SARS-CoV-2 has evolved to enhance viral fitness and immune evasion.

scholarly journals Neutralizing antibodies for the prevention and treatment of COVID-19

2021 ◽  
Author(s):  
Lanying Du ◽  
Yang Yang ◽  
Xiujuan Zhang
Keyword(s):  
Neutralizing Antibodies ◽  
Virus Entry ◽  
Infection Process ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Prevention And Treatment ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

AbstractSevere 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.

scholarly journals Perspectives on the development of neutralizing antibodies against SARS-CoV-2

2020 ◽  
Vol 3 (2) ◽  
pp. 109-114 ◽  
Author(s):  
Mitchell Ho
Keyword(s):  
Neutralizing Antibodies ◽  
Respiratory Infections ◽  
Human Cells ◽  
Primary Target ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Single Domain Antibodies ◽  
Viral Membrane Fusion ◽  
Viral Surface ◽  
Selection Of

Abstract SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective.

scholarly journals Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

2021 ◽  
Author(s):  
Micah Rapp ◽  
Yicheng Guo ◽  
Eswar R. Reddem ◽  
Lihong Liu ◽  
Pengfei Wang ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Neutralizing Antibodies ◽  
Structural Basis ◽  
List Type ◽  
Receptor Binding Domain ◽  
Heavy Chains ◽  
Vh Gene ◽  
Antibody Class ◽  
Insight Into ◽  
Potent Neutralization

SUMMARYAntibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD-up and -down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycan N343 on a neighboring RBD – a quaternary interaction accommodated by an increase in RBD separation of up to 12 Å. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component specifying recognition of RBD and CDRH3 component specifying quaternary interactions.HighlightsDetermine structures of VH1-2-derived antibodies 2-43, 2-15, and H4 in complex with SARS-CoV-2 spikeDefine a multi-donor VH1-2-antibody class with modular components for RBD and quaternary recognitionReveal structural basis of RBD-up and RBD-down recognition within the classShow somatic hypermutations and avidity to be critical for potencyDelineate changes in spike conformation induced by CDRH3-mediated quaternary recognition

scholarly journals Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicholas K. Hurlburt ◽  
Emilie Seydoux ◽  
Yu-Hsin Wan ◽  
Venkata Viswanadh Edara ◽  
Andrew B. Stuart ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Substantial Reduction ◽  
Affinity Maturation ◽  
Structural Basis ◽  
Binding Motif ◽  
Neutralization Potential ◽  
Neutralizing Monoclonal Antibody ◽  
Potent Neutralization

Abstract SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determine the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain. The structure reveals that CV30 binds to an epitope that overlaps with the human ACE2 receptor binding motif providing a structural basis for its neutralization. CV30 also induces shedding of the S1 subunit, indicating an additional mechanism of neutralization. A germline reversion of CV30 results in a substantial reduction in both binding affinity and neutralization potential indicating the minimal somatic mutation is needed for potently neutralizing antibodies against SARS-CoV-2.

scholarly journals A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

Science ◽  
2020 ◽  
Vol 368 (6496) ◽  
pp. 1274-1278 ◽  
Author(s):  
Yan Wu ◽  
Feiran Wang ◽  
Chenguang Shen ◽  
Weiyu Peng ◽  
Delin Li ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Complex Structure ◽  
Structural Basis ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Interface ◽  
Neutralizing Capacity ◽  
Rational Vaccine Design ◽  
Therapeutic Study

Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.

scholarly journals NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge

2020 ◽  
Author(s):  
Mimi Guebre-Xabier ◽  
Nita Patel ◽  
Jing-Hui Tian ◽  
Bin Zhou ◽  
Sonia Maciejewski ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Cynomolgus Macaque ◽  
Full Length ◽  
List Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Lower Infection ◽  
Pulmonary Pathology ◽  
Ongoing Phase

ABSTRACTThere is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988).HighlightsFull-length SARS-CoV-2 prefusion spike with Matrix-M1™ (NVX-CoV2373) vaccine.Induced hACE2 receptor blocking and neutralizing antibodies in macaques.Vaccine protected against SARS-CoV-2 replication in the nose and lungs.Absence of pulmonary pathology in NVX-CoV2373 vaccinated macaques.

scholarly journals Structural basis for the recognition of the 2019-nCoV by human ACE2

2020 ◽  
Author(s):  
Renhong Yan ◽  
Yuanyuan Zhang ◽  
Yingying Guo ◽  
Lu Xia ◽  
Qiang Zhou
Keyword(s):  
Amino Acid ◽  
Pairwise Comparison ◽  
Full Length ◽  
Structural Basis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Neutral Amino Acid Transporter ◽  
Extracellular Peptidase

AbstractAngiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter B0AT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 Å in the presence of B0AT1. The local resolution at the ACE2-RBD interface is 3.5 Å, allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.

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