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Convergent Evolution Of COVID Threatens Old and New Antibody Therapies

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A new study published today is the first to investigate the consequences of numerous mutations on the evolution of SARS-CoV-2 variants.

The findings can assist scientists in better comprehending the features of existing and future variants.

Additionally, the information can be used to better inform the development of vaccines and medicines to combat the dangers posed by mutations.

“Earlier studies, including ours, have focused on explaining the effect of single mutations and not the mechanism underlying the co-evolution of mutations,” says professor Krishna Mallela.

This new research “helps explain the concept of convergent evolution by balancing positive and negative selection pressures,” he continues.

The paper, published in the journal Biochemistry and authored by Mallela’s lab’s Vaibhav Upadhyay, Casey Patrick, Alexandra Lucas, explains why approved antibody therapies, such as those for Omicron and its subvariants, are failing to neutralize recent variants of concern.

“Understanding the mechanisms underlying the antibody escape and the location of mutations in the spike protein,” according to Mallela can “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.”

According to the findings, certain mutations arise repeatedly in developing variants exhibiting convergent evolution. In the spike protein’s receptor binding domain, this evolution occurs at three amino acid positions: K417, E484, and N501 (RBD). Nearly half of the 4.3 million variant sequences in the GISAID database with any of these three mutations also have all three. Individual mutations have both advantageous and deleterious/adverse consequences, but when they are combined, the deleterious/adverse effects are canceled out, resulting in better selection of the mutations as a whole.

The researchers investigated the physical mechanisms underlying the convergent evolution of the three mutations by determining the effects of mutations on binding to the angiotensin-converting enzyme 2 receptors, immune escape from neutralizing antibodies, protein stability, and expression on an individual and collective basis.

They discovered that the three RBD mutations play highly distinct and specific functions in boosting virus fitness, which supports their positive selection, despite the fact that individual mutations have harmful effects that make them vulnerable to negative selection.

K417T is immune to Class 1 antibodies and has higher stability and expression than the wild type, however, it has lower ACE2 receptor binding. Although E484K is immune to Class 2 antibodies, it has lower receptor binding, stability, and expression.

Although N501Y improves receptor binding, it decreases receptor stability and expression. The harmful effects of these mutations are minimized when they occur simultaneously due to compensatory actions.

K417T/E484K/N501Y is a triple mutant that exhibits enhanced ACE2 receptor binding, avoids both Class 1 and Class 2 antibodies, and has similar stability and expression to the wild type.

The scientists conclude that the combined effect of numerous mutations is considerably more beneficial to virus fitness than individual mutations, and that having multiple mutations boosts individual mutation selection.

“As SARS-CoV-2 has evolved from Alpha to Omicron, more and more mutations are accumulating,” Mallela concludes, adding “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.”

Image Credit: Getty

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