'Tailor-made pocket feature shared by coronaviruses causing disease'

LONDON: Scientists have discovered that a tailor-made pocket within the SARS-CoV-2 spike protein, which is capable of binding itself to the human cell surface, is what results in some coronaviruses causing severe disease.

An international team of researchers scrutinised the spike glycoproteins decorating all coronaviruses. During the study, the researchers found that while the tailor-made pocket was present in all deadly coronaviruses, including MERS and Omicron, the feature was missing in variants which cause mild infection with cold-like symptoms.

Researchers of the study, led by University of Bristol, said their findings could lead to the development of a treatment to defeat all coronaviruses — from the 2002 SARS-CoV outbreak to Omicron, the current variant of SARS-CoV-2, and dangerous variants that may emerge in future.

The findings of the study have been published in a journal, ‘Science Advances’.

The team said their findings suggested that the pocket bound a small molecule, linoleic acid — an essential fatty acid indispensable for many cellular functions including inflammation and maintaining cell membranes in the lungs so that humans can breathe properly.

This pocket could now be exploited to treat all deadly coronaviruses and at the same time render them vulnerable to a linoleic acid-based treatment targeting this pocket.

Covid-19, caused by SARS-CoV-2, is the third deadliest coronavirus outbreak following SARS-CoV in 2002 and MERS-CoV in 2012.

The much more infectious SARS-CoV-2 continues to infect people and damage communities and economies worldwide, with new variants of concern emerging successively, and Omicron evading vaccination and immune response.

“In our earlier work, we identified the presence of a small molecule, linoleic acid, buried in a tailor-made pocket within the SARS-CoV-2 glycoprotein, known as the ‘Spike protein’, which binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage,” explained Christiane Schaffitzel from School of Biochemistry, University of Bristol.

“We showed that binding linoleic acid in the pocket could stop virus infectivity, suggesting an anti-viral treatment. This was in the original Wuhan strain that started the pandemic.

“Since then, a whole range of dangerous SARS-CoV-2 variants have emerged, including Omicron, the currently dominating variant of concern. We scrutinised every new variant of concern and asked whether the pocket function is still present,” said Schaffitzel.

Omicron has undergone many mutations, enabling it to escape immune protection offered by vaccination or antibody treatments that lag behind this rapidly evolving virus. While everything else may have changed, the researchers found that the pocket remained virtually unaltered, also in Omicron, the study said.

“When we realised that the pocket we had discovered remained unchanged, we looked back and asked whether SARS-CoV and MERS-CoV, two other deadly coronaviruses causing previous outbreaks years ago, also contained this linoleic acid binding pocket feature,” said Christine Toelzer, lead author of the study.

The team applied high-resolution electron cryo-microscopy, cutting-edge computational approaches and cloud computing.

Their results showed that SARS-CoV and MERS-CoV also had the pocket, and could bind the ligand, linoleic acid, by a virtually identical mechanism.

“In our current study, we provide evidence that the pocket remained the same in all deadly coronaviruses, from the first SARS-CoV outbreak 20 years ago to Omicron today,” said Schaffitzel.

“We have shown previously that linoleic acid binding to this pocket induces a locked spike, abrogating viral infectivity. We also show now that linoleic acid supplementation suppresses virus replication inside cells.

“We anticipate that future variants will also contain the pocket, which we can exploit to defeat the virus,” concluded Schaffitzel.