Life Style

Two potent SARS-CoV-2 neutralizing antibodies effective against B.1.351 and B.1.1.7 mutants

By analyzing the cryoEM structure of the antibody against the SARS-CoV-2 virus, researchers found that the neutralizing ability of the two antibodies targeted the region of the virus away from the ACE2 binding region, thus affecting the new strain. I am reporting that I will not receive it.

As the COVID-19 pandemic continued to spread around the world, several new mutations emerged in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Of note are the B.1.1.7 strain found in the United Kingdom (UK) and the B.1.351 that emerged in South Africa in late 2020. The B.1.1.7 variant is now widespread in more than 50 countries, both of which are believed to increase the transmission of the virus.

Some studies Neutralizing antibodyNeutralizing antibodies specifically directed to the N-terminal domain have less effect on these mutants. However, many antibodies to the viral receptor binding domain (RBD) appear to retain most of their potency.

In a previous study, researchers reported two very potent RBD antibodies, 1-57 and 2-7, but their effects were not inhibited by the new mutant. To understand how effective these antibodies are against new strains, they investigated their structure using a cryo-electron microscope (EM).They report their results in a research treatise published in bioRxiv* Preprint server.

Antibodies 1-57 utilize hydrophilic pockets to accommodate the emerging strain mutant E484K. (A) Cryo-EM reconstruction of the spike complex with antibodies 1-57 from two orthogonal views. A single conformation with all RBDs down is observed. NTDs are shown in orange, RBDs are shown in green, glycans are shown in red, antibody heavy chains are shown in blue, and light chains are shown in gray. (B) A 1-57 domain-level view complexed with RBD. Newly emerging mutants are highlighted in red. (C) Details of antibody 1-57 recognition of RBD showing the overall interface (left panel), recognition by CDR H3 (center panel), and recognition by CDR L1 and L2 (right panel). CDRs H1, H2, and H3 are colored in shades of blue. CDRs L1, L2, and L3 are colored in shades of gray. The E484 is highlighted in bright red (right panel). Nitrogen atoms are color-coded in blue and oxygen atoms in red. Hydrogen bonds (distance <3.2 Å) are represented by dashed lines.

Antibodies 1-57 utilize hydrophilic pockets to accommodate the emerging strain mutant E484K. (A) Cryo-EM reconstruction of the spike complex with antibodies 1-57 from two orthogonal views. A single conformation with all RBDs down is observed. NTDs are shown in orange, RBDs are shown in green, glycans are shown in red, antibody heavy chains are shown in blue, and light chains are shown in gray. (B) A 1-57 domain-level view complexed with RBD. Newly emerging mutants are highlighted in red. (C) Details of antibody 1-57 recognition of RBD showing the overall interface (left panel), recognition by CDR H3 (center panel), and recognition by CDR L1 and L2 (right panel). CDRs H1, H2, and H3 are colored in shades of blue. CDRs L1, L2, and L3 are colored in shades of gray. The E484 is highlighted in bright red (right panel). Nitrogen atoms are color-coded in blue and oxygen atoms in red. Hydrogen bonds (distance <3.2 Å) are represented by dashed lines.

Understanding antibody binding complexes

Use of SARS-CoV-2 Spike protein The team formed a complex with antibody 1-57 and reconstructed the structure at a resolution of 3.42 Å (about 3/10 billion meters).They identified three single conformations antigen-Binding fragments per trimer. Each fragment was bound to RBD in a down configuration.

The main interaction between RBD and the antibody was via CDR H3, forming disulfide bonds, hydrophobic interactions, and hydrogen bonds. Of the mutations in the UK and South Africa mutants, only the South African strain E484K was close to the 1-57 binding site. Structural modeling revealed that the lysine residue is geometrically compatible with the 1-57 bond.

For 2-7 antibodies, cryoEM analysis revealed that three fragments were bound to a single spike, two were bound to an up-structured RBD, and one was bound to a down-structured RBD. It was. Interactions with RBD were primarily residues 438-451 and 495-502. CDR H2 formed hydrogen bonds with several salt bridges. In the UK and South African mutations, antibody 2-7 bound only near N501.

Antibodies 1-57 and 2-7 used heavy chain genes and were less frequent in the SARS-CoV-2 specific antibody group. This suggests that antibodies genetically similar to 1-57 and 2-7 may be uncommon in human response to the virus.

The portion of the virus that is often the target of antibodies can cause the virus to develop an evasion mechanism. Using the previously reported structure of the antibody-RBD complex, the authors found that the epitopes of antibodies 1-57 and 2-7 were less frequently targeted. These epitopes are also in regions that are not important for binding to angiotensin converting enzyme (ACE2) or neutralizing antibody escapes.

Antibodies 1-57 and 2-7 were unaffected by RBD mutations in UK and South Africa mutants, but other RBD mutations may affect them. For example, mutations at positions 452 and 494 can affect 1-57 binding, and mutations at position 439 can affect 2-7 binding. However, further investigation is needed to better understand this.

Comparison of 1-57 and 2-7 epitopes with antibody classes exemplifying high frequency responses. Frequency per residue recognized by 52 known RBD-directed antibodies. The VH1-2 and VH3-53 / 66 antibody classes recognize RBD residues with high targeting frequency. 1-57 and 2-7 recognize RBD residues that are less frequently targeted.

Some antibodies are effective against mutant strains

To understand whether SARS-CoV-2 escape mutations were selected by neutralizing antibodies and antibody resistance mutations were due to antibody selection, the team correlated location mutation frequency with antibody recognition frequency. They had a higher mutation frequency at the most frequently targeted residues, but found only a weak correlation between the two.

The authors found a strong correlation between the frequency of RBD mutations and their effect on ACE2-binding affinity. This suggests that RBD mutations result from the benefits of ACE2 binding selection and may help the virus bind more strongly to ACE2.

However, most RBD mutations are detrimental to ACE2 binding, so the virus may have limited options for avoiding antibody neutralization. This may explain similar mutations in different SARS-CoV-2 strains.

“Our analysis suggests that potent antibodies 2-7 and 1-57 may not exert much selective pressure on the circulating strains, resulting in resistance variants to these two antibodies. It’s less likely to happen, “the author writes.

These two antibodies bind to the viral region rather than the ACE2-binding region, and their neutralizing ability is less sensitive to mutations, which may be a good candidate for developing long-term protective therapies. ..

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.

Two potent SARS-CoV-2 neutralizing antibodies effective against B.1.351 and B.1.1.7 mutants

Source link Two potent SARS-CoV-2 neutralizing antibodies effective against B.1.351 and B.1.1.7 mutants

Back to top button