The new peer-reviewed paper can help inform the development of new vaccines and therapeutics
A new study published in today's issue of Biochemistry is the first to explore the effects of multiple mutations in the evolution of SARS-CoV-2 variants. The findings can 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 counter the threats posed by variants.
"Earlier studies, including ours, have focused on explaining the effect of single mutations and not the mechanism underlying the co-evolution of mutations," said the paper's corresponding author Krishna Mallela, PhD, professor in the department of pharmaceutical sciences at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences located on the University of Colorado Anschutz Medical Campus.
"Our study helps explain the concept of convergent evolution by balancing positive and negative selection pressures," he adds.
The new paper, co-authored by Vaibhav Upadhyay, Casey Patrick and Alexandra Lucas from Mallela's lab, was featured on the journal's cover. The paper provides the physical basis for why approved antibody therapeutics are not working in neutralizing the recent variants of concern, such as Omicron and its subvariants.
"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," said Mallela.
The study found that certain mutations appear repeatedly in emerging variants showing convergent evolution. One such evolution occurs in Beta, Gamma and Omicron variants at three amino acid positions K417, E484 and N501 in the spike protein's receptor binding domain (RBD). 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 researchers 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.
They found the three RBD mutations perform very distinct and specific roles that contribute toward improving the virus fitness and build the case for the positive selection of these mutations.
The authors conclude 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.
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."
