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Vulnerability of SARS-CoV-2RBD discovered-antibody target against variant

Vulnerability of SARS-CoV-2RBD discovered-antibody target against variant

 


Scientists are developing a vaccine to protect individuals from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the pandemic of coronavirus disease 2019 (COVID-19). Succeeded. However, all currently available COVID-19 vaccines are designed based on the ancestral SARS-CoV-2 strain that emerged in 2019.

Study: A broad and potent neutralizing epitope of SARS-related coronavirus. Biophysics and computational biology. Image Credits: Natalya Rozhkova / Shutterstock.com

study: A broad and potent neutralizing epitope of SARS-related coronavirus.Biophysics and Computational Biology.. Image Credits: Natalya Rozhkova / Shutterstock.com

Background

Previous studies have shown that the COVID-19 vaccine elicits an immune response, reducing the severity of the disease and the incidence of infection. In addition, vaccination reduced the hospitalization rate for COVID-19.

Since 2019, several SARS-CoV-2 variants have emerged due to continuous genomic mutations. These variants are classified as Variant of Concern (VOC) and Variant of Concern (VOI) according to infection rate, pathogenicity, and ability to circumvent immune defenses induced by either vaccination or spontaneous infection. It has been.

Currently, SARS-CoV-2 Omicron VOC is the predominant circulating strain in the world and is known to be resistant. Neutralizing antibody (NAb) Reaction induced after COVID-19 vaccination.

Reduced efficacy of the most approved therapeutic monoclonal antibodies and their mixtures, such as BRII-196, LY-CoV555, REGN10987, REGN10933, and LY-CoV016, has also been reported against Omicron infections. Therefore, there is an urgent need for effective vaccines and / or treatments that can provide a wider range of protection against current and future SARS-CoV-2VOC and VOI.

Normally, the neutralizing potency and the width of the antibody are considered to be mutually exclusive. Most of the current nAbs used in the treatment of COVID-19 target the angiotensin converting enzyme 2 (ACE2) receptor binding site (RBS) of the SARS-CoV-2 spike (S) protein. Therefore, SARS-CoV-2 mutants usually contain most of the mutations in the RBS region, making nAbs less effective.

Previous studies have shown that nAbs such as CR3022, which can target other epitopes on the receptor binding domain (RBD), also show reduced neutralization potency against SARS-CoV-2 mutants. It has been.

About research

new Biophysics and Computational Biology Research has succeeded in identifying a strong neutralizing epitope associated with SARS. coronavirus (CoV) Includes SARS-CoV-1, WIV1 and SHC014. In this study, scientists identified regions on the RBD of the SARS-CoV-2S protein targeted by diverse groups of antibodies. In addition, the therapeutic antibody ADG20 has been shown to neutralize SARS-CoV-2VOC and other CoVs such as the Omicron variant.

A previous study showed that ADG20 neutralization of the Omicron mutant was reduced by a factor of 20 compared to the Delta mutant. This antibody was determined to be the most effective of several therapeutic antibodies.

The Omicron (BA.1) variant has evolved to produce BA.2 (B.1.1.529.2) sublineage. Compared to Omicron BA.1 sublineage, BA.2 contains one return (S446G) and three additional mutations, T376A, D405N, and R408S, along with other mutations such as S371F instead of S371L in RBD. It has been.

Recent studies have shown that BA.2 evades ADG20 and other antibodies that target this site, such as S2X259. This may be due to the difference in interaction between residues 371 and N343 glycans.

Many therapeutic antibodies have been developed against SARS-CoV-2, some of which include sotrovimab, REGEN-COV, Evusheld, and bebutellobimab. Of these antibodies, bebutellobimab was found to be the most effective against both Omicron BA.1 and BA.2. However, it turns out that Evusheld is effective against BA.2 but not against BA.1.

A common area of ​​RBD that is a powerful and wide range of nAb targets for SARS-CoV-2. (A) Dispersion plot of antibody neutralizing potency (IC50, ng / mL) against (top) ancestral SARS-CoV-2 and (bottom) Omicron vs. neutralizing width. This is defined by the number of SARS-related CoV strains neutralized in it. Studies (a total of 10 strains including the ancestors SARS-CoV-2, alpha, beta, delta, gamma, mu, omicron, SARS-CoV-1, pang17, and WIV1). (B) All powerful and broad nAbs target areas that span the RBS (green) and proximal CR3022 sites (yellow) from one end. The epitope of each antibody is surrounded by a black line (top), the variable domains of ADG20, K398.22, and S2X259 are shown cartoonly, and a dark turquoise heavy chain and a light cyan light chain (bottom) are shown. increase. Epitopes and RBSs have a BSA of> 0 Å2 calculated by PISA (50) using the structures of ADG20 (this study), K398.22 (26), S2X259 (PDB 7RAL) (57), CR3022 (PDB 6W41). Defined by the residue of. ) (9), S309 (PDB 6WPS) (24), and ACE2 (PDB 6M0J) (54). As shown at the bottom of the panel, SARS-CoV-2 mutants and SARS-CoV-1 can be neutralized by these antibodies.” class =”rounded-img” src =”https://d2jx2rerrg6sh3.cloudfront.net/images/news/ImageForNews_718767_16571624823649187.jpg” srcset =”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/2000/src/images/news/ImageForNews_718767_16571624823649187.jpg 2000w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443 /ri/1950/src/images/news/ImageForNews_718767_16571624823649187.jpg 1950w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/1750/src/images/news/ImageForNews_718767_16571624823649187.jpg //d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/1550/src/images/news/ImageForNews_718767_16571624823649187.jpg 1550w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ ri / 1350 / src / images / news / ImageForNews_718767_16571624823649187.jpg 1350w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/1150/src/images/news/ImageForNews_718767_16571624823649187.jpg //d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/950/src/images/news/ImageForNews_718767_16571624823649187.jpg 950w, h ttps: //d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/750/src/images/news/ImageForNews_718767_16571624823649187.jpg 750w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443 /ri/550/src/images/news/ImageForNews_718767_16571624823649187.jpg 550w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220706105443/ri/450/src/images/news/ImageForNews_718767_16571624823649187.jpg 450w” sizes =”(min-width: 1200px) 673px, (min-width: 1090px) 667px, (min-width: 992px) calc (66.6vw -60px), (min-width: 480px) calc (100vw -40px), calc (100vw) –30px)” style =”width: 2000px; height: 935px;” width =”2000″ height =”935″/><em>A common area of ​​RBD that is a powerful and wide range of nAb targets for SARS-CoV-2. (A) Dispersion plot of antibody neutralizing potency (IC50, ng / mL) against (top) ancestral SARS-CoV-2 and (bottom) Omicron vs. neutralizing width. This is defined by the number of SARS-related CoV strains neutralized in it. Studies (a total of 10 strains including the ancestors SARS-CoV-2, alpha, beta, delta, gamma, mu, omicron, SARS-CoV-1, pang17, and WIV1). (B) All powerful and broad nAbs target areas that span the RBS (green) and proximal CR3022 sites (yellow) from one end. The epitope of each antibody is surrounded by a black line (top), the variable domains of ADG20, K398.22, and S2X259 are shown cartoonly, and a dark turquoise heavy chain and a light cyan light chain (bottom) are shown. increase. Epitopes and RBSs have a BSA of> 0 Å2 calculated by PISA (50) using the structures of ADG20 (this study), K398.22 (26), S2X259 (PDB 7RAL) (57), CR3022 (PDB 6W41). Defined by the residue of. ) (9), S309 (PDB 6WPS) (24), and ACE2 (PDB 6M0J) (54). As shown at the bottom of the panel, SARS-CoV-2 mutants and SARS-CoV-1 can be neutralized by these antibodies.</em></p> <h2>Survey results</h2> <p>Current studies report several mutations associated with Omicron variants that have reduced the ability of existing antibodies to neutralize. For example, LY-CoV016 binds to RBS-A of several SARS-CoV-2 variants and promotes neutralizing activity. However, for the Omicron variant, this variant contains the mutant K417N, so no neutralization occurs. This will result in the loss of the salt bridge.</p> <p>Similarly, previous studies have reported that the antibodies AZD8895, REGN10933, and LY-CoV555 bind to SARS-CoV-2 RBS-B and promote neutralization. However, the presence of certain mutations in the Omicron variant, such as E484A and Q493R, results in the loss of polar interactions and reduced neutralization of these antibodies. In addition, the N440K mutation in the Omicron mutant reduced the ability of AZD1061, REGN10987, and LY-CoV1404 to bind to the RBS-D site. </p> <p>The S371F mutation in BA.2 sublineage reduces the ability of sotrovimab to neutralize. Therefore, this antibody is effective against BA.1.</p> <p>The results of the current study are consistent with the structural observations of previous studies that reported reduced or abolished neutralization of AZD8895 against BA.2.12.1, BA.4, and BA.5.</p> <p>A class of long CDRH3 antibodies with the YYDRxG motif was discovered that targeted the highly conserved CR3022 site. This antibody can block ACE2 without binding directly to RBS. Such antibodies have exceptional efficacy against a wide range of SARS-CoV-2VOC and salvecoviruses.</p> <h2>Conclusion</h2> <p>In the current study, the authors identified vulnerable sites in SARS-CoV-2RBD that could be targeted by the antibody. This alleviates the challenges associated with mutations that reduce antibody efficiency.</p> <div class=

Journal reference:

  • Formerly M. , Zhu, X. , He, W. , et al. (2022) A broad and potent neutralizing epitope of SARS-related coronavirus. Biophysics and computational biology. Biophysics and Computational Biology 119 (29) e2205784119.. doi: 10.1073 / pnas.2205784119

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