New research reveals the physical basis for which approved antibody therapies do not work to neutralize recent concerns of COVID-19 concern, such as Omicron and its subvariants.
The new peer-reviewed paper can help inform the development of new vaccines and therapeutics.
When SARS-CoV-2 first appeared, the virus that causes COVID-19 disease was a single variant. Over time, the coronavirus evolved and new variants emerged, such as Alpha, Beta, Delta, Gamma and Omicron. Unfortunately, researchers have found that vaccines and therapeutics are sometimes much less effective against some of these variants.
But why? In a new study, scientists investigated the physical basis of why approved antibody therapies do not work to neutralize recent concerns about COVID-19, such as Omicron and its subvariants.
A new study published in the June 7, 2022 issue of the journal Biochemistry is the first to explore the effects of multiple mutations on the evolution of SARS-CoV-2 variants. The findings may help scientists better understand the properties of current and new variants.
The results can also be used to better inform the development of vaccines and therapeutics to counteract the threats posed by variants.
“Previous studies, including ours, have focused on explaining the effect of individual mutations and not the mechanism underlying the coevolution of mutations,” said Krishna Mallela, PhD, a professor of Department of Pharmaceutical Sciences at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences located on the Anschutz Medical Campus of the University of Colorado.
“Our study helps explain the concept of convergent evolution by balancing positive and negative selection pressures,” he adds.
The cover of Biochemistry. The convergent evolution of multiple mutations improves SARS-CoV-2 viral fitness by balancing positive and negative selection and improves the chances of mutation selection together. Credit: Biochemistry
The new article, co-authored by Vaibhav Upadhyay, Casey Patrick and Alexandra Lucas from Mallela’s lab, appeared on the cover of the magazine. The paper provides the physical basis for why approved antibody therapies do not work to neutralize recent variants of concern, such as Omicron and its subvariants.
“Understanding the mechanisms underlying antibody escape and the location of ear protein mutations will help develop new antibody therapies that work against new variants by targeting epitopes with minimal mutations or developing broad neutralizing antibodies that target multiple epitopes, “Mallela said.
“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 drive research and development. of new therapies to better combat new variants “. – Krishna Mallela, PhD
The study found that certain mutations appear repeatedly in emerging variants that show convergent evolution. One of these evolutions occurs at three positions of amino acids K417, E484, and N501 in the receptor-binding domain (RBD) of the ear protein. Nearly half of the 4.3 million variant sequences in the GISAID database that contain any of these three mutations have all three occurring together. Although individual mutations have both beneficial and harmful / adverse effects, when combined, the harmful / adverse effects are nullified, leading to a better selection of mutations together.
The researchers examined the physical mechanisms underlying the convergent evolution of the three mutations by delineating the individual and collective effects of the mutations on receptor 2 binding of the angiotensin-converting enzyme, the immune leakage of neutralizing antibodies. protein stability and expression.
They found that all three RBD mutations perform very different and specific functions that help improve the fitness of the virus and promote its positive selection, although individual mutations have harmful 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, binding to the ACE2 receptor has decreased. E484K escapes Class 2 antibodies; however, receptor binding, stability, and expression have decreased. N501Y increases receptor binding; however, stability and expression have decreased. When these mutations come together, the harmful effects are mitigated due to the presence of compensatory effects. The triple mutant K417T / E484K / N501Y has increased binding to the ACE2 receptor, escapes both class 1 and class 2 antibodies, and has a stability and expression similar to that of the wild-type.
The authors conclude that the collective effect of these mutations is much more advantageous for virus fitness than individual mutations and the presence of multiple mutations improves the selection of individual mutations.
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 drive research. and the development of new therapies to better combat new variants. “
Reference: “The convergent evolution of multiple mutations improves the viral fitness of SARS-CoV-2 variants by balancing positive and negative selection” by Vaibhav Upadhyay, Casey Patrick, Alexandra Lucas and Krishna MG Mallela, May 5, 2022, Biochemistry.DOI: 10.1021 / acs.biochem.2c00132