University of British Columbia scientists unveil the world’s first molecular

Image: the atomic structure of the variant spike protein Omicron (purple) bound to the human ACE2 receptor (blue).
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Credit: University of British Columbia College of Medicine

Researchers at the University of British Columbia School of Medicine have performed the world’s first molecular-level structural analysis of the variant spike protein Omicron. The results were published today in Science.

The analysis, performed at sub-atomic resolution using cryo-electron microscopy, reveals how the highly mutated Omicron variant binds to and infects human cells.

“Understanding the molecular structure of the viral spike protein is important as it will allow us to develop more effective therapies against Omicron and related variants in the future,” said lead author Dr Sriram Subramaniam (he/she), Professor in the UBC Department of UBC. Biochemistry and molecular biology. “By analyzing the mechanisms through which the virus infects human cells, we can develop better treatments that disrupt this process and neutralize the virus.”

The spiky protein, found on the outer surface of the coronavirus, enables SARS-CoV-2 to enter human cells. The Omicron variant contains 37 unprecedented spike protein mutations – three to five times more than previous variants.

Structural analysis revealed that several mutations (R493, S496, and R498) create new salt bridges and hydrogen bonds between the spike protein and the human cell receptor known as ACE2. The researchers conclude that these new links appear to increase the affinity of the link – how strongly the virus attaches to human cells – while the other mutations (K417N) decrease the strength of this bond.

“Overall, the results show that Omicron has greater binding affinity than the original virus, at levels more comparable to what we see with the delta variant,” said Dr. Subramaniam. “Remarkably, the Omicron variant has evolved to retain its ability to bind to human cells despite these widespread mutations.”

The researchers conducted further experiments that showed that the Omicron spike protein increases antibody evasion. In contrast to previous variants, Omicron showed measurable evasion of all six monoclonal antibodies tested, with complete evasion of five. The variant also showed increased evasion of antibodies collected from vaccinated individuals and unvaccinated COVID-19 patients.

Notably, Omicron was less elusive to vaccine-induced immunity, compared to immunity from natural infection in unvaccinated patients. “This suggests that vaccination remains our best defense,” Dr. Subramaniam said.

Based on the observed increase in binding affinity and antibody avoidance, the researchers say that spike protein mutations are likely contributing factors to the increased transmissibility of the Omicron variant.

Next, Dr. Subramaniam says his research team will leverage this knowledge to support the development of more effective treatments.

“An important focus of our team is to understand the association of 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.”

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