scholarly journals Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

Science ◽  
2021 ◽  
Vol 371 (6531) ◽  
pp. 823-829 ◽  
Author(s):  
C. Garrett Rappazzo ◽  
Longping V. Tse ◽  
Chengzi I. Kaku ◽  
Daniel Wrapp ◽  
Mrunal Sakharkar ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Human Monoclonal Antibody ◽  
Binding Activity ◽  
Lung Pathology ◽  
Receptor Binding Site ◽  
Binding Domains ◽  
Large Panel ◽  
Clade 1 ◽  
Conserved Epitope ◽  
Strong Binding Activity

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

scholarly journals An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

2020 ◽  
Author(s):  
C. Garrett Rappazzo ◽  
Longping V. Tse ◽  
Chengzi I. Kaku ◽  
Daniel Wrapp ◽  
Mrunal Sakharkar ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Binding Activity ◽  
Lung Pathology ◽  
Murine Models ◽  
Receptor Binding Site ◽  
Binding Domains ◽  
Treatment And Prevention ◽  
Conserved Epitope ◽  
Strong Binding Activity

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.

scholarly journals A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

Science ◽  
2020 ◽  
Vol 368 (6491) ◽  
pp. 630-633 ◽  
Author(s):  
Meng Yuan ◽  
Nicholas C. Wu ◽  
Xueyong Zhu ◽  
Chang-Chun D. Lee ◽  
Ray T. Y. So ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
Receptor Binding Site ◽  
S Protein ◽  
Antibody Recognition ◽  
Binding Domains ◽  
Binding Epitope ◽  
Cryptic Epitope ◽  
Conserved Epitope

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resolution. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the “up” conformation and slightly rotated. These results provide molecular insights into antibody recognition of SARS-CoV-2.

scholarly journals Tight Binding of Influenza Virus Hemagglutinin to Its Receptor Interferes with Fusion Pore Dilation

2002 ◽  
Vol 76 (24) ◽  
pp. 12405-12413 ◽  
Author(s):  
Masanobu Ohuchi ◽  
Reiko Ohuchi ◽  
Tatsuya Sakai ◽  
Akira Matsumoto
Keyword(s):  
Influenza Virus ◽  
Binding Site ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Deletion Mutant ◽  
Binding Activity ◽  
Side Chains ◽  
Fusion Activity ◽  
Receptor Binding Site ◽  
Fusion Pores

ABSTRACT Deletion of oligosaccharide side chains near the receptor binding site of influenza virus A/USSR/90/77 (H1N1) hemagglutinin (HA) enhanced the binding of HA to erythrocyte receptors, as was also observed with A/FPV/Rostock/34 (H7N1). Correlated with the enhancement of binding activity, the cell fusion activity of HA was reduced. A mutant HA in which three oligosaccharide side chains were deleted showed the highest level of binding and the lowest level of fusion among the HAs tested. The cell fusion activity of the oligosaccharide deletion mutant of HA, however, was drastically elevated when the binding activity was reduced by deletion of four amino acids adjacent to the receptor binding site. Thus, a reciprocal relationship was observed between the receptor binding and the cell fusion activities of H1/USSR HA. No difference was observed, however, in lipid mixing activity, so-called hemifusion, between wild-type (WT) and oligosaccharide deletion mutant HAs. Soluble dye transfer testing showed that even the HA with the lowest cell fusion activity was able to form fusion pores through which a small molecule such as calcein could pass. However, electron microscopic studies revealed that a large molecule such as hemoglobin hardly passed through the fusion pores formed by the mutant HA, whereas hemoglobin did efficiently pass through those formed by the WT HA. These results suggested that interference in the process of dilation of fusion pores occurs when the binding of HA to the receptor is too tight. Since the viral nucleocapsid is far larger than hemoglobin, appropriate receptor binding affinity is important for virus entry.

scholarly journals Targeted isolation of panels of diverse human broadly neutralizing antibodies against SARS-like viruses

2021 ◽  
Author(s):  
Wan-ting He ◽  
Rami Musharrafieh ◽  
Ge Song ◽  
Katharina Dueker ◽  
Sean Callaghan ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Selection Strategy ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
Large Panel ◽  
Effective Design ◽  
Original Virus

SUMMARYThe emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy 1–7. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed 8,9. Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone 10–13. Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and also show strong binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against SARS-CoV-2 VOCs compared to the original virus. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination 14–18. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a basis for effective design of pan-sarbecovirus vaccines.

scholarly journals Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient

2020 ◽  
Author(s):  
Daming Zhou ◽  
Helen ME Duyvesteyn ◽  
Cheng-Pin Chen ◽  
Chung-Guei Huang ◽  
Ting-Hua Chen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Economic Impact ◽  
Receptor Binding ◽  
Late Stage ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Receptor Binding Site ◽  
Conserved Epitope

AbstractThe COVID-19 pandemic has had unprecedented health and economic impact, but currently there are no approved therapies. We have isolated an antibody, EY6A, from a late-stage COVID-19 patient and show it neutralises SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds tightly (KD of 2 nM) the receptor binding domain (RBD) of the viral Spike glycoprotein and a 2.6Å crystal structure of an RBD/EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues of this epitope are key to stabilising the pre-fusion Spike. Cryo-EM analyses of the pre-fusion Spike incubated with EY6A Fab reveal a complex of the intact trimer with three Fabs bound and two further multimeric forms comprising destabilized Spike attached to Fab. EY6A binds what is probably a major neutralising epitope, making it a candidate therapeutic for COVID-19.

scholarly journals A Second Receptor Binding Site on Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Contributes to Activation of the FusionMechanism

2007 ◽  
Vol 81 (7) ◽  
pp. 3216-3228 ◽  
Author(s):  
Matteo Porotto ◽  
Micaela Fornabaio ◽  
Glen E. Kellogg ◽  
Anne Moscona
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Cell Interaction ◽  
Binding Activity ◽  
Viral Fusion ◽  
Receptor Binding Site ◽  
Computational Data ◽  
Human Parainfluenza Virus ◽  
Type 3 ◽  
Entry Receptor

ABSTRACT The hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out three discrete activities that each affect the ability of HN to promote viral fusion and entry: receptor binding, receptor cleaving (neuraminidase), and triggering of the fusion protein. The interrelationship between the receptor binding and fusion-triggering functions of HN has not been clear. For human parainfluenza type 3 (HPIV3), one bifunctional site on HN can carry out both receptor binding and neuraminidase activities, and this site's receptor binding can be inhibited by the small receptor analog zanamivir. We now report experimental evidence, complemented by computational data, for a second receptor binding site near the HPIV3 HN dimer interface. This second binding site can mediate receptor binding even in the presence of zanamivir, and it differs from the second receptor binding site of the paramyxovirus Newcastle disease virus in its function and its relationship to the primary binding site. This second binding site of HPIV3 HN is involved in triggering F. We suggest that the two receptor binding sites on HPIV3 HN each contribute in distinct ways to virus-cell interaction; one is the multifunctional site that contains both binding and neuraminidase activities, and the other contains binding activity and also is involved in fusion promotion.

scholarly journals Studies on the different conditions for rabies virus neutralization by monoclonal antibodies #1-46-12 and #7-1-9

2002 ◽  
Vol 83 (12) ◽  
pp. 3045-3053 ◽  
Author(s):  
Takashi Irie ◽  
Akihiko Kawai
Keyword(s):  
Monoclonal Antibodies ◽  
Rabies Virus ◽  
Receptor Binding ◽  
Binding Activity ◽  
Host Cells ◽  
Virus Neutralization ◽  
Escape Mutant ◽  
Virus Infectivity ◽  
Receptor Binding Site ◽  
Viral Receptor

Virus-neutralizing activity of two monoclonal antibodies (mAbs), #7-1-9 and #1-46-12, against rabies virus glycoprotein (G) was compared. Although these mAbs affected the virion’s ability to bind to host cells similarly, a big difference was found in the titres of virus neutralization (1:7132 and 1:32 for mAbs #1-46-12 and #7-1-9, respectively, at a concentration of 10 μg protein/ml). Although no big difference in virion-binding affinity between the two mAbs was found, the number of antibodies required for virus neutralization was very low, ⩽20 molecules for mAb #1-46-12 and ⩾250 molecules for mAb #7-1-9. In the latter case, the mAbs cover a major part of the virion surface and cause steric hindrance of viral receptor-binding activity. The infectivity of an epitope-preserved escape mutant virus (R-61) was not affected by the binding of high numbers of mAb #1-46-12 to the virion, which implies that mAb binding does not mask the receptor-binding site of the viral spikes. Based on these results, it is hypothesized that mAb #1-46-12 affected virus infectivity by a mechanism different from covering the virion spikes. Possible virus-neutralizing mechanisms by low numbers of mAb #1-46-12 in comparison to that of mAb #7-1-9 are discussed.

scholarly journals Structural Insight into a Human Neutralizing Antibody against Influenza Virus H7N9

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
Cong Chen ◽  
Liguo Liu ◽  
Yan Xiao ◽  
Sheng Cui ◽  
Jianmin Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Receptor Binding ◽  
Influenza A ◽  
Human Monoclonal Antibody ◽  
H7n9 Virus ◽  
Receptor Binding Site ◽  
Fragment Antigen Binding ◽  
Insight Into

ABSTRACT Since its first emergence in East China in early 2013, many cases of avian influenza A H7N9 have been reported. The disease has extended to 22 provinces in mainland China and some surrounding areas. Strategies to combat viral infection are urgently needed. We previously isolated a human monoclonal antibody, HNIgGA6, that neutralized the H7N9 virus both in vitro and in vivo . In this study, we determined the crystal structure of viral hemagglutinin (HA) globular head bound to the fragment antigen-binding region (Fab) of HNIgGA6. The crystal structure shows that the tip of the HNIgGA6 heavy-chain complementarity-determining region 3 (HCDR3) directly interposes into the receptor binding site (RBS) and mimics, in many respects, the interaction of the sialic acid receptor. Three residues at Y98, H183, and E190, which are critical to human cellular receptor binding, are also essential for HNIgGA6 recognition. Meanwhile, dual mutations at V186G and L226Q in RBS were able to disrupt viral HA1 binding with the antibody. Our study provides a better understanding of the mechanism for protective antibody recognition and a sound foundation for the design of therapeutic drugs and vaccines against H7N9 influenza. IMPORTANCE Neutralization by antibody is one of the most important mechanisms for a host to defend against viral infections. Human-originated antibody HNIgGA6 was generated in response to the natural infectious H7N9 virus and showed potential for use in suppression of H7N9 infection, with possible therapeutic implications. The crystal structure of the HNIgGA6/HA1 complex provided new insight into the protective immune response to H7N9 virus in humans, as well as possibilities for the development of effective H7N9 pandemic vaccines and antiviral molecules.

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