Novel mutations that are able to reach high frequencies in SARS-CoV-2 genomes are possible due to the degree of sexual error of the SNA-CoV-2 RNA reproduction process. The increase in these variables could affect the development of vaccines and treatment as they spread throughout the population.
Furthermore, in order to prevent promising vaccines or prophylactics or antibody-based medications, it is essential to understand how and whether SARS-CoV-2 may develop immune-dependent immunity. avoid antibody.
The researchers studied the immunodominant SARS-CoV-2 RBM, a component of the receptor binding domain (RBD) that mediates viral entry and is a key target of neutralizing antibodies in the body. They found that the circulation of viruses was a highly variable area of the spike protein, making up the top 10% of entropy (mutation rate). Overall, the findings suggest that the RBM is capable of accepting amino acid modifications without disturbing the human angiotensin-converting enzyme 2 (ACE2) binding.
Effect of RBM mutations in SARS-CoV-2
In particular, the team attempted to elucidate the clinical and epidemiological effect, molecular characteristics, and immune response to the RBM N439K receptor – cytosine-to-adenine translocation in the third codon condition, following to amino acid conversion from asparagine to lysine. This variation was first identified in March 2020 in Scotland, and as of January 2021, there are two lines. This mutation has been observed in over 30 countries and is the second most common RBD mutation in the world, and the sixth most common spike mutation.
A position similar to N439K in the SARS-CoV RBM forms a ACE2 salt bridge with positively charged amino acids, according to the team. Therefore, they hypothesized that the N439K SARS-CoV-2 variant could be a similar salt bridge at the RBD-ACE2 interface. They determined the crystal x-ray structure of the N439K RBD with ACE2 at a resolution of 2.8 å and found that the salt bridge does. Thus, the N439K mutation may add strength to the interaction at the binding interface.
They then evaluated the effect of bovine on viral fitness by examining clinical data and results related to the virus carrying N439K mutation, as well as in vitro data. The researchers found that the association associated with a disease-like clinical spectrum and viral loads is slightly higher in vivo compared to viruses with the wild-type N439 residue.
“One important finding from this paper is the level of variability found in the immunodominant RBM on the spike protein,” lead author Gyorgy Snell, PhD, senior director of structural biology at Vir Biotechnology, said in a statement.
Resistance to monoclonal antibodies
Finally, the researchers tested whether N439K mutation induces immune suppression by a protective medium. To do this, they evaluated the efficacy of monoclonal antibodies and polyclonal immunosuppressive serum from 442 recovered individuals, including six donors who were infected with the SARS-CoV-2 N439K variant, to N439K RBD recognition. Of those, 6.8% of the sera tested showed a more than double reduction in binding to N439K RBD compared to controls.
To further understand the effect of budding on monoclonal antibody binding, the scientists screened a panel of 140 monoclonal antibodies separated from individuals who survived SARS-CoV-2 infection, which is a representative sample of the antibodies targeting RBD generated after infection, as well as therapeutic antibodies that are in clinical stage development or have already been approved for emergency use consent (REGN10933, REGN10987, LY-CoV555, and S309 ).
Overall, 16.7% of monoclonal antibodies showed a more than two-fold reduction of RBD binding in response to the N439K shift. RBD binding competition tests with ACE2 and three structurally differentiated epitopes on the RBD showed that monoclonal antibodies sensitive to N439K were enriched for one of the epitopes (S2H14 / site I) and showed no ACE2 inhibition. This is consistent with the N439K mutation setting at the edge of the RBM.
Importantly, N439K mutation allowed pseudoviruses to resist neutralization with a monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for emergency use as part of a dual-antibody cocktail (LY-CoV555). Opposition to a single antibody in a cocktail may reduce the overall effectiveness of the treatment as monotherapy, according to the authors.
To reduce the effect of monoclonal antibody escape mutations of SARS-CoV-2, the authors suggested that researchers must develop monoclonal antibodies with epitopes that are highly resistant to viral escape, such as conserved epitopes. outside the RBM, or screening other patients for the presence of variable changes before drugs are administered.
An additional challenge for the study of SARS-CoV-2, according to Snell, is the limited level of classification. With more than 90 million cases of COVID-19 reported, only about 350,000 virus types have been traced.
“That’s only 0.4% – just the tip of the iceberg,” Snell explained. “This reinforces the need for a broad study, a detailed understanding of the molecular mechanisms of mutations, and for the development of high-barrier therapies against current and emerging changes.”
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