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COVID-19 Research

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Overview of COVID-19 Research on Octet Platforms

At ForteBio, we are determined to support the worldwide effort of researchers to find much needed cures and vaccines for the SARS-Cov2 virus. As part of our commitment, we have compiled links and resources to more information, including how our Octet systems have been used in recent publications in the Resources tab. Since the COVID-19 sequence was first shared in January, Octet system data has been featured in several breakthrough publications related to coronavirus biology, vaccine, and antiviral therapeutic development.

The following summary table provides some important research articles where Octet systems have played a role in elucidating binding kinetics and affinity, neutralization, cross-blocking or titer of COVID-19 virus particles. As new information becomes available, we will update this table and other information on this page to provide the latest information.

 

Analyte(s)

Immobilized Ligand(s)

Virus species

Assay Focus

Biosensor

Reference

ACE2

Fc-tagged SARS CoV-2 RBD

SARS CoV-2

Cross-reactivity and receptor binding

AHC

[1]

ACE2

SARS-CoV-2 SB SARS-CoV SB

SARS CoV-2

Receptor binding

HIS1K

[2]

mAb, MERS S protein, VHH

SARS CoV-2 S1, SARS CoV-2 RBD

SARS CoV-2

VHH and mAb binding assessment, Epitope binning

AR2G

[3]

Fab, IgG

SARS CoV-2 S protein, SARS CoV-2 RBS

SARS CoV-2

FAB, IgG binding characterization

HIS1K

[4]

ACE2, SARS-CoV RBD

SARS-CoV-specific neutralizing antibodies

SARS CoV-2

Cross-reactivity binding

SA

[5]

Antibodies

Biotin-Recombinant SARS-CoV S1 protein

SARS CoV-2

Neutralization antibody assessment

SA

[6]

FAB, ACE2, SARS S protein

mAb, ACE2

SARS CoV-2

Receptor binding, antibody reactivity, competition assays

AHC, HIS1K

[7]

SARS CoV-2 RBD

Inhibitor Peptide

SARS CoV-2

Peptide inhibitor development

SA

[8]

mAb

S1B and SARS Secto domains

SARS CoV and SARS CoV-2

Antibody reactivity assessment

HIS1K

[9]

SARS CoV-2 RBD, SARS CoV RBD, mAbs, FAB

mAbs, SARS CoV-2 RBD, SARS CoV RBD

SARS CoV and SARS CoV-2

Antibody binding characterization, epitope binning, competition binding

Protein A, HIS2, HIS1K

[10]

Coronavirus S proteins

Biotin-9OAc6SLN

SARS CoV and MERS CoV

Receptor binding

SA

[11]

MERS-5HB fusion inhibitor

Biotin-peptide (MERS-HR2P)

MERS CoV

Protein Inhibitor development

SA

[12]

mAb, MERS S protein

mAb, MERS S protein

MERS CoV

Epitope binning and Receptor binding

SAX, Protein A

[13]

MERS-CoV S

mAbs

MERS CoV

Antibody reactivity measurements, competition assays

AHC, HIS1K

[14]

MERS-CoV NTD, mutants

mAb

MERS CoV

Antibody reactivity measurements

AHC

[15]

MERS S-protein

mAbs

MERS CoV

Antibody reactivity measurements

AHC

[16]

RBD,S1,S2 domains

Vaccine-induced mouse monoclonal IgGs

MERS CoV

Antibody reactivity and epitope binning

AHC, HIS1K

[17]

FABs

MERS-CoV RBD

MERS CoV

Epitope binning

HIS1K

[18]

 

Binding Kinetics Characterization

Ying et. al. from Fudan University, Shanghai, in collaboration with others at the Wuhan Institute of Virology reportedly assessed the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV. They reported for the first time, using data obtained on ForteBio Octet system, that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). Such results are critical to the eventual development of effective antiviral therapeutics and vaccines.

Similar observations were reported by, Joyce et. al. using a high-resolution crystal structure of the SARS-CoV-2 S RBD. Antibodies that were known to interact with SARS-CoV and MERS CoV RBD were tested for SARS-CoV-2 binding activity using an Octet system. Only two antibodies, 240CD and CR3022 out of the pool displayed low nano-molar binding affinities against the SARS-CoV 2 RBD.

Ying et. al. at Fudan University published another article that describes the generation and testing of single domain antibodies targeting SARS-Cov-2 RBD. The panning using SARS-CoV-2 RBD and S1 as antigens resulted in the identification of antibodies targeting five types of neutralizing or non-neutralizing epitopes on SARS-CoV-2 RBD. Eighteen of them were selected for further studies. They bound potently and specifically to the SARS-CoV-2 RBD with subnanomolar to nanomolar affinities as measured by bio-layer interferometry (BLI) and ELISA

Rapid determination of virus binding and cross-reactivity

In their article on single domain antibodies targeting SARS-Cov-2 RBD, Ying et. al. tested 18 human single-domain antibodies in competition binding assays using the Octet system and found that they could be divided into three competition groups (group A, B or C) that did not show any competition with each other.

Insights into COVID-19 binding epitopes

Bio-Layer Interferometry (BLI) technology is helping scientists around the world learn more about the recent Coronavirus (COVID-19) outbreak. In this flyer we highlight two of the many cases where researchers are using the Octet® system to understand the virus's binding mechanisms as a first step in the development of a vaccine.

A fast and high precision influenza vaccine potency assay

A fast and accurate determination of vaccine titer during manufacturing is important in understanding vaccine development process performance, and for correctly scaling each process step. The Octet platform combines the high-throughput characteristics of a 96-well or 384-well plate format with improvements in precision and reproducibility and is derived from a simpler and more direct vaccine/antigen–antibody binding measurement method. They provide process development groups with a robust and easy to use alternative to the SRID method. BLI reduces the assay time from days to just a few hours for a 96-well plate of samples.

Aptamer Group utilizes Octect Red384 for accurate results

The last few months of research has highlighted the S1 protein of SARS CoV-2 as a lead target for therapeutics. A team of Aptamer Group successfully isolated a monoclonal aptamer capable of selectively binding the S1 protein of SARS CoV-2 spike. They used the Octet Red384 to test the aptamer against SARS CoV-2 and related viruses and also to identify aptamers that bound the protein at different sites. Read more...

Resources of COVID-19 Research

Global research on Covid-19 gathered by the World Health Organization (WHO) and updated daily.

The Allen Institute for AI has partnered with leading research groups to prepare and distribute the COVID-19 Open Research Dataset (CORD-19), a free resource of over 52,000 scholarly articles, including over 41,000 with full text, about COVID-19 and the coronavirus family of viruses for use by the global research community. Online, full text search of the database can be accessed at the link below. A search of publications referencing use of ForteBio products in virus research can also be performed.

A curated list of open funding calls and other support for researchers, non-profit organizations, and commercial organizations, specifically for COVID-19 and coronavirus-related research is maintained and updated daily.

The National Institutes of Health (NIH) lists all coronavirus related funding opportunities.

Application Note A Fast and High Precision Influenza Vaccine Potency Assay

Mall molecule and peptide therapeutic drugs are highly sought after in most areas of disease research due to their desirable pharmacological properties and low propensity for immunogenicity. In small molecule drug discovery, the path to lead molecules can stem from many sources or starting points including fragment screening, high throughput screening, de novo structural design, etc. The determination and evaluation of the affinity of small molecule binding to a therapeutic target is a significant component of the drug discovery process and lead optimization. The hit-to-lead and lead optimization process are essential to accurately determine biological potency in vitro so that structure-activity relationships (SAR) can be used for efficient structural design. Learn how Octet RED96e, Octet RED384, Octet HTX and Pioneer SPR platforms can be used to characterize small molecule and peptide systems.

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Application Note Cross-competition or Epitope Binning Assays on the Octet HTX System

In early drug development, cross-competition assays are used to characterize hundreds of antibody clones and can be performed with hybridoma supernatants, phage lysates or purified samples. Because mAbs in different bins bind to distinct epitopes and display diverse functional characteristics, epitope binning studies can increase the likelihood of choosing a lead antibody with the desired biological activity. Cross-competition assays also are performed to identify mAbs that bind similar epitopes to a previously characterized mAb as in the generation of biosimilars or biobetters. These assays may also be useful in selecting reagents for sandwich or ELISA-type assays, such as those used for biomarker testing or pharmacodynamic assays, to identify good antibody pairs that bind to the antigen simultaneously.

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Application Note Octet Potency Assay: Development, Qualification and Validation Strategies

In this application note, we discuss the strategies for the development and validation of a potency assay using Octet® systems. We have highlighted the Octet system’s ease-ofuse and fast time to results by showcasing strategies for the development and validation of a method for evaluating the binding of an Fc gamma receptor III molecule to the widely characterized NISTmAb.

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Flyer Recent insights into COVID-19 binding epitopes

The novel coronavirus, COVID-19, has been declared a pandemic by the world health organization (WHO). As it spreads, researchers are mobilizing to understand the virus’s binding mechanisms as a first step in the development of a vaccine. Below are examples of recent publications highlighting insights into these binding mechanisms.

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Infographics Understanding COVID-19 Vaccine and Therapeutic Development Research

Studying antibodies generated from Covid-19 infections and vaccines can provide invaluableinformation towards therapeutic antibody development and engineering. Affinity, kinetics, and epitope interrelationships are important factors in vaccine and therapeutic design.

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Infographics Detecting SARS-CoV-2 Antibodies in Serum and Plasma Samples

Convalescent plasma therapy is a potential treatment under investigation where antibodies from recovered patients are transfused to current COVID-19 patients with the intent to help them fight the infection and buy time until their immune system can produce antibodies. However, not all recovered persons have the same amount of antibody titers suitable for such transfusions. Reliable, simple, and rapid methods are needed to assess relative antibody titers in plasma samples.

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Publications Immunoglobulin fragment F(ab’)2 against RBD potently neutralizes SARS-CoV-2 in vitro

Xiaoyan Pan, et al., April 2020

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Publications An antibody against the F glycoprotein inhibits Nipah and Hendra virus infections

Dang HV et al., 26(10):980-987, Nat Struct Mol Biol. Oct. 2019

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Publications Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein

Haixia Zhou, et al., 10, Article number: 3068, Nature Communications 2019

Most neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) target the receptor-binding domain (RBD) of the spike glycoprotein and block its binding to the cellular receptor dipeptidyl peptidase 4 (DPP4). The epitopes and mechanisms of mAbs targeting non-RBD regions have not been well characterized yet. Here we report the monoclonal antibody 7D10 that binds to the N-terminal domain (NTD) of the spike glycoprotein and inhibits the cell entry of MERS-CoV with high potency. Structure determination and mutagenesis experiments reveal the epitope and critical residues on the NTD for 7D10 binding and neutralization. Further experiments indicate that the neutralization by 7D10 is not solely dependent on the inhibition of DPP4 binding, but also acts after viral cell attachment, inhibiting the pre-fusion to post-fusion conformational change of the spike. These properties give 7D10 a wide neutralization breadth and help explain its synergistic effects with several RBD-targeting antibodies.

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Publications Structural basis for human coronavirus attachment to sialic acid receptors

M. Alejandra Tortorici, et al.,  26, pages481–489, Nature Structural & Molecular Biology 2019

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Publications Towards a solution to MERS_protective human mAb targeting different domains and functions of the MERS-coronavirus spike glycoprotein

Ivy Widjaja, et al., 8(1): 516–530., Emerging Microbes and Infections 2019

The Middle-East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus that causes severe and often fatal respiratory disease in humans. Efforts to develop antibody-based therapies have focused on neutralizing antibodies that target the receptor binding domain of the viral spike protein thereby blocking receptor binding. Here, we developed a set of human monoclonal antibodies that target functionally distinct domains of the MERS-CoV spike protein. These antibodies belong to six distinct epitope groups and interfere with the three critical entry functions of the MERS-CoV spike protein: sialic acid binding, receptor binding and membrane fusion. Passive immunization with potently as well as with poorly neutralizing antibodies protected mice from lethal MERS-CoV challenge. Collectively, these antibodies offer new ways to gain humoral protection in humans against the emerging MERS-CoV by targeting different spike protein epitopes and functions.

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Publications Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

Walls AC, et al., 176(5):1026-1039.e15., Cell Feb. 2019

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Publications Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on MERS-CoV spike to avoid neutralization escape

Wang L, et al., 92(10). pii: e02002-17, Joural of Virology, April 2018

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Publications Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Daniel Wrapp, et al., Vol. 367, Issue 6483, pp. 1260-1263 , Science  13 Mar 2020

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Publications Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on MERS-CoV spike to avoid neutralization escape

Lingshu Wang, et al., 92(10). pii: e02002-17., Journal of Virology, April 2018

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Publications Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

Xiaolong Tian, et al., 9(1): 382–385, Emerg Microbes Infect. 2020

The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. These results suggest that CR3022 may have the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.

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Publications Inhibition of Flaviviruses by Targetinga Conserved Pocket on the Viral Envelope Protein. Cell Chemical Biology

de Wispelaere M, et al., 25(8):1006-1016.e8, Cell Chemical Biology, Aug. 2018

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Publications SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development

Chunyun Sun, et al.,  February 2020

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Publications Ultrapotent Human Neutralizing Antibody Repertoires Against Middle East Respiratory Syndrome Coronavirus From a Recovered Patient

Niu P, et al., 218(8):1249-1260, Journal of Infectious Disease, Sept. 2018

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Publications A human monoclonal antibody blocking SARS-CoV-2 infection

Chunyan Wang, et al., March 2020

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Publications Effects of Active Site Inhibitors on APN-dependent Coronavirus Entry

Y.Cai, University of Minnesota M.S. thesis. June 2017

Aminopeptidase N(APN) has been shown as a receptor of several coronaviruses, such as HCoV-229E, TGEV, CCoV and FeCoV. Bestatin and Actinonin are inhibitors which can block APN enzymatic activity. These inhibitors bind to the catalytic site of APN, while viruses bind to the outer surface of APN. Here we investigate the mechanism of APN inhibition on protein-protein binding, receptor expression and coronavirus entry. We find that these chemical compounds can inhibit the protein-protein interaction between APN and Coronavirus spike; these inhibitors can also regulate APN RNA and protein expression; additionally, these compounds can inhibit the pseudovirus entry of HCoV-229E into human cells at a certain level. Additionally, coronavirus spike-treated human cells show a decrease in APN expression. This phenomenon may reveal an adaptation of cells to the different treatments and conditions. Our research may provide a new potential strategy for antiviral treatment.

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Publications The first-in-class peptide binder to the SARS-CoV-2 spike protein

G. Zhang, et al., March 2020

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Publications Identification of a novel inhibitor against middle east respiratory syndrome Coronavirus Viruses

Sun Y, et al., 9(9). pii: E255, Viruses Sept. 2017

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (KD) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC50) of about 1 μM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable α-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent.

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Publications A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein

M. Gordon Joyce, et al, March 2020

SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease—COVID-19— within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronavirus’s surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 Å. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the “closed” prefusion S structure, but is accessible in “open” conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates and provide a framework for the accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related beta coronaviruses.

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Publications Evaluation of candidate vaccine approaches for MERS-CoV

Wang L, et al., 28;6:7712, Nature Communications, July 2015

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.

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Publications Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Alexandra C. Walls, et al, pii: S0092-8674(20)30262-2 Cell March 2020

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Publications Identification of human neutralizing antibodies against MERS_CoV and their role in virus adaptive evolution

Tang XC, et al., 111(19):E2018-26., Proc Natl Acad Sci U S A., May 2014

In this report, the authors screened a human Ab-phage library using a novel panning strategy to identify seven neutralizing antibodies against Middle East Respiratory Syndrome coronavirus (MERS-CoV) which causes severe respiratory disease with ~43% mortality. They further defined key residues that impacted receptor binding, viral fitness and had neutralizing effects leading to new possibilities for human mAb-based immunotherapies. Binding studies were performed on the Oct RED96 using Anti-FLAG biosensors.

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

Meng Yuan, et al., March 2020

The outbreak of COVID-19, which is caused by SARS-CoV-2 virus, continues to spread globally, but there is currently very little understanding of the epitopes on the virus. In this study, we have determined the crystal structure of the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein in complex with CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient. CR3022 targets a highly conserved epitope that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding site can only be accessed when at least two RBDs on the trimeric S protein are in the “up” conformation. Overall, this study provides structural and molecular insight into the antigenicity of SARS-CoV-2.

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Publications Quan Zhua , Ralph S. Baricb,c,2, and Wayne A. Marascoa,2. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution

Xian-Chun Tanga, et al., 111 (19) E2018-E2026, PNAS May 13, 2014

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Publications Structural and functional analysis of a potent sarbecovirus neutralizing antibody

Dora Pinto, et al., April 2020

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Application Overview Octet Bio-Layer Interferometry systems: Advancing development of coronavirus vaccine and therapeutics

Millions of people have been infected worldwide with the virus, and hundreds of thousands of deaths reported so far. The rapidly evolving epidemiology of the pandemic and absence of a licensed therapeutic or vaccine for the disease has accelerated the need to develop an intervention. 

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