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Source: SARS-CoV-2 Mutations K417, E484 And N501   Jun 07, 2022  19 days ago
University of Colorado Study Shows Mutations K417, E484 And N501 Found On Most Of The Emerging SARS-CoV-2 Variants Causes Antibody Treatments To Be Redundant!
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University of Colorado Study Shows Mutations K417, E484 And N501 Found On Most Of The Emerging SARS-CoV-2 Variants Causes Antibody Treatments To Be Redundant!
Source: SARS-CoV-2 Mutations K417, E484 And N501   Jun 07, 2022  19 days ago
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 team 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.
 
The study findings showed 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.
 
When compared to the wild-type Wuhan strain, 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 Wuhan strain.
 
The study findings 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.
 
The study findings were published in the peer reviewed journal: Bioschemistry.
https://pubs.acs.org/doi/10.1021/acs.biochem.2c00132#
 
The study findings can be used to better inform the development of vaccines and therapeutics to counter the threats posed by variants.
 
Corresponding and lead author, Dr Krishna Mallela, Ph.D told Thailand Medical News, "Earlier studies, including ours, have focused on explaining the effect of single mutations and not the mechanism underlying the co-evolution of mutations. Our study helps explain the conc ept of convergent evolution by balancing positive and negative selection pressures.”



The study was supported by other researchers including by Dr Vaibhav Upadhyay, Dr Casey Patrick and Dr Alexandra Lucas from Professor Mallela's lab.
 
The study findings provide the physical basis for why approved antibody therapeutics are not working in neutralizing the recent variants of concern, such as Omicron and its subvariants.
 
Professor Mallela added, "Understanding the mechanisms underlying the antibody escape and the location of mutations in the spike protein will help in developing new antibody therapeutics that will work against new variants by targeting epitopes with minimal mutations or developing broad neutralizing antibodies that target multiple epitopes.”
 
The research findings showed that certain mutations appear repeatedly in emerging variants showing convergent evolution. One such evolution occurs at three amino acid positions K417, E484 and N501 in the spike protein's receptor binding domain (RBD). Nearly half of 4.3 million variant sequences in GISAID database that contain any of these three mutations have all three occurring together. Although individual mutations have both beneficial and deleterious/adverse effects, when they come together, deleterious/adverse effects get canceled out, leading to improved selection of the mutations together.
 
The study team examined the physical mechanisms underlying the convergent evolution of the three mutations 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.
 
The study team found the three RBD mutations perform very distinct and specific roles that contribute toward improving the virus fitness and build the case for their positive selection, even though individual mutations have deleterious effects that make them prone to negative selection.
 
Interestingly when compared to the wild-type Wuhan strain, K417T escapes Class 1 antibodies and has increased stability and expression; however, it has decreased ACE2 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 ACE2 receptor binding, escapes both Class 1 and Class 2 antibodies and has similar stability and expression as that of the wild-type.
 
The study team concluded that the collective effect of these mutations is far more advantageous for virus fitness than the individual mutations and the presence of multiple mutations improves the selection of individual mutations.
 
Professor Mallela concludes, "As SARS-CoV-2 has evolved from Alpha to Omicron, more and more mutations are accumulating. We hope that by providing research that understands the role of these mutations, we can help further propel research and the development of new therapies to better combat new variants."
 
For more on SARS-CoV-2 Mutations And Emerging Variants, keep on logging to Thailand Medical News.
 

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