A team of researchers, including a scientist of Indian origin at the prestigious University of British Columbia, has become the first in the world to perform a molecular-level structural analysis of the spike protein Omicron, which could help accelerate the development of more effective treatments against the variant.
The spike protein helps the virus to enter and infect cells.
Omicron has greater binding affinity than the original SARS-CoV-2 virus, at levels more comparable to what was seen with the delta variant, said Dr. Sriram Subramaniam, a professor in the UBC School of Medicine’s Department of Biochemistry and Molecular Biology.
The findings, published in Science, shed new light on why Omicron is so highly transmissible and will help accelerate the development of more effective treatments, according to a statement from the Vancouver-based university.
The analysis, performed at nearly atomic resolution using a cryo-electron microscope, reveals how the mutant variant severely infects human cells and is highly immune evading, Mr Subramaniam discussed the implications of his team’s research and emphasized that “vaccination remains our best defense against the Omicron variant”.
The university said the results show strong antibody evasion and binding to human cells that contribute to increased transmissibility, and that vaccination remains the best defense.
“UBC researchers are the first to perform a structural analysis at the molecular level of the omicron variant spike protein,” she added.
“The Omicron variant is unprecedented for having 37 spike protein mutations, which is three to five times more mutations than any other variant we’ve seen,” said Dr. Subramaniam.
This is important for two reasons. First, because the spike protein is how the virus attaches to and infects human cells. Second, because the antibodies stick to the spike protein to neutralize the virus, he said.
Therefore, small mutations on the spike protein have potentially big implications for how the virus is transmitted, how our bodies fight it, and the effectiveness of treatments.
“Our study used cryo-electron microscopy and other tests to understand how mutations affect the behavior of the Omicron variant at the molecular level,” said Dr. Subramaniam.
He said that several mutations (R493, S496 and R498) create new salt bridges and hydrogen bonds between the spike protein and a human cell receptor known as ACE2.
Subramaniam said this appears to increase the affinity of the link, and how strongly the virus attaches to human cells, while the other mutations (K417N) decrease the strength of that bond.
Remarkably, he said, the Omicron variant has evolved to retain its ability to bind to human cells efficiently despite these widespread mutations.
“Our experiments confirm what we see in the real world, which is that the Omicron spike protein is much better than other variants at avoiding monoclonal antibodies that are commonly used as therapeutics, as well as at evading immunity stemming from both vaccines and natural infection,” he said.
Omicron was less elusive to vaccine-induced immunity, he said, compared to immunity from natural infection in unvaccinated COVID-19 patients.
He said that both properties seen as a consequence of elevated protein mutations, strong binding to human cells and avoidance of increased antibodies, are likely contributing factors to the increased transmissibility of the Omicron variant.
These are the underlying mechanisms that fuel the variant’s rapid spread and why Omicron could become the dominant variant of SARS-CoV-2 so quickly, he said.
“The good news is that knowing the molecular structure of the spike protein will allow us to develop more effective treatments against Omicron and related variants in the future. Understanding how the virus attaches to and infects human cells means we can develop treatments that disrupt this process and neutralize the virus.”
“An important focus of our team is to better understand the association between neutralizing antibodies and the therapies that will be effective across a full range of variables, and how they can be used to develop antiviral therapies,” Subramaniam added.
Omicron was first identified in South Africa and Botswana in November and is leading the current wave of infections.
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