SARS-CoV-2 mutations K417 – E484 – N501 found on most of the emerging SARS-CoV-2 variants are causing current antibody treatments to be ineffective

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A new study by researchers from University of Colorado Anschutz Medical Campus has shown that the SARS-CoV-2 mutations K417, E484 And N501 found on most of the emerging SARS-CoV-2 variants are causing current antibody treatments to be ineffective and redundant.

The new study led by Dr Krishna Mallela, Ph.D., Professor in the department of pharmaceutical sciences at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences unravels why COVID-19 antibody treatments aren’t as effective for new variants and is the first study to explore the effects of multiple mutations in the evolution of SARS-CoV-2 variants. The findings can help medical scientists better understand the properties of current and new variants.
 
Currently, multiple mutations have been seen to undergo convergent evolution in SARS-CoV-2 variants of concern.
 
It was found that one such evolution occurs in Beta, Gamma, and Omicron variants at three amino acid positions K417, E484, and N501 in the receptor binding domain of the spike protein.

The study findings were published in the peer reviewed journal: Bioschemistry.
https://pubs.acs.org/doi/10.1021/acs.biochem.2c00132#

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We examined the physical mechanisms underlying the convergent evolution of three mutations K417T/E484K/N501Y by delineating the individual and collective effects of mutations on binding to angiotensin converting enzyme 2 receptor, immune escape from neutralizing antibodies, protein stability, and expression.

Our results show that each mutation serves a distinct function that improves virus fitness supporting its positive selection, even though individual mutations have deleterious effects that make them prone to negative selection. Compared to the wild-type, K417T escapes Class 1 antibodies and has increased stability and expression; however, it has decreased receptor binding. E484K escapes Class 2 antibodies; however, it has decreased receptor binding, stability, and expression.

N501Y increases receptor binding; however, it has decreased stability and expression. When these mutations come together, the deleterious effects are mitigated due to the presence of compensatory effects. Triple mutant K417T/E484K/N501Y has increased receptor binding, escapes both Class 1 and Class 2 antibodies, and has similar stability and expression as that of the wild-type.

These results show that the convergent evolution of multiple mutations enhances viral fitness on different fronts by balancing both positive and negative selection and improves the chances of selection of mutations together.

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