U of T researchers find vulnerability in COVID-19 variants that reduces transmissibility

Researchers at the University of Toronto have found that Omicron variants of the COVID-19-causing virus can be hindered in their ability to infect people by mutations in the spike protein that prevent the virus from binding to and entering cells.

The spike protein is a distinctive feature of viruses, found on their outside surface. The researchers found that mutations in this protein influence the sensitivity of Omicron variants to chemical reduction – a process that can prevent Omicron variants from spreading and could potentially be delivered to patients through aerosol therapy.

“While infection by the Omicron variant usually leads to milder symptoms, this variant is unique in how easily it can spread,” said Zhong Yao, lead author on the study and senior research associate in the lab of Igor Stagljar, a professor at U of T’s Donnelly Centre for Cellular and Biomolecular Research.

“Our study clearly demonstrates a significant vulnerability of Omicron to chemical reduction – one that is either not found or is much less potent in previous variants of coronavirus.”

The team's findings were published in the Journal of Molecular Biology.

The researchers found that Omicron-specific mutations in the virus’s spike protein reduce its ability to bind to a key receptor in host cells, called ACE2. The spike protein’s receptor-binding domain, the surface of which comes into contact with the ACE2 receptor, consists of multiple disulfide bonds. Two of these bonds, involving the C480-C488 and C379-C432 disulfides, are highly susceptible to cleavage through chemical reduction, the team showed.

The internal environment of a cell is in a naturally reduced state compared to the surface, and does not usually support disulfides bonds. In contrast, extracellular proteins and protein domains contain disulfide bonds that are oxidized, creating a structural conformation that helps them bind to receptors.

Breaking disulfide bonds changes the conformation of the proteins, so they can no longer fit into their receptors. Treating the Omicron spike protein with a reducing agent breaks the disulfide bonds at the surface, inhibiting the spike protein from binding to the ACE2 receptor.

“While mutations, in general, have increased the transmissibility of Omicron subvariants, as well as their ability to evade the immune system, this vulnerability to disulfide cleavage presents potential target areas for treating Omicron infections,” said Stagljar, who is also a professor of biochemistry and molecular genetics at U of T’s Temerty Faculty of Medicine.

One potential treatment method that takes advantage of Omicron’s structural vulnerability is aerosol therapy. Reducing agents can be toxic to the body at higher levels and can potentially harm non-target proteins. Aerosol therapy overcomes this obstacle by delivering the reducing agent directly to the lungs, which can tolerate a higher concentration level of the reducing agent than the rest of the body.

The researchers found that Omicron variants were particularly sensitive to an antioxidant called bucillamine, which is in a Phase 3 clinical trial by Revive Therapeutics to evaluate its safety and efficacy.

“While Omicron is less deadly overall, it still poses a threat to older, immunocompromised and unvaccinated groups,” Yao said.

“It’s helpful to understand the mechanism through which Omicron variants are transmitted between people, so that we can harness it for therapeutic treatments and be more prepared.”

The research was supported by the PRiME COVID-19 Task Force, COVID Relief, the Toronto COVID-19 Action Fund and the Temerty Knowledge Translation grant.