Science Advances: Pocket features common to deadly coronaviruses can be used for pan-coronavirus antiviral treatments

Scientists have discovered why some coronaviruses are more likely to cause serious illness, which has been a mystery until now
.
Researchers at the University of Bristol, led in the study, published in Scientific Advances, say their findings could lead to the development of a pan-coronavirus treatment to defeat all coronaviruses – from the SARS-CoV outbreak in 2002 to the current SARS-CoV-2 variant Omicron, and potentially dangerous variants
that may emerge in the future.

In the new study, an international team led by Professor Christiane Schaffitzel of the University of Bristol scrutinized the spike glycoprotein
that adorns all coronaviruses.
They first revealed a custom-made pocket signature in the SARS-CoV-2 spike protein in all deadly coronaviruses, including MERS-MERS and Omegalon.

In sharp contrast, pocket features are not present in coronavirus, which causes mild infections with cold-like symptoms
.

The team says their findings show that this pocket can bind a small molecule linoleic acid — an important fatty acid essential for many cellular functions, including inflammation and maintaining lung cell membranes to allow us to breathe normally — and can now be used to treat all deadly coronaviruses, while leaving them vulnerable to basic treatment of linoleic acid that targets this pocket
.

COVID-19 caused by SARS-CoV-2 is the third deadliest coronavirus outbreak
after SARS-CoV in 2002 and MERS-CoV in 2012.
The more contagious SARS-CoV-2 continues to infect humans, destroying communities and economies around the world, new variants of concern are emerging, and omicrons evade vaccination and immune responses
.

Professor Schaffitzel, from the University of Bristol's School of Biochemistry, explains: "In our earlier work, we discovered the presence of a small molecule linoleic acid, which is buried in a bespoke pocket of coronavirus type 2 glycoprotein, known as the 'spike protein', which binds to the surface of human cells, allowing the virus to penetrate the cell and begin to replicate, causing extensive damage
.

"We demonstrated that combining linoleic acid in the pocket can stop infection of the virus, which means an antiviral treatment
.
This is the Wuhan strain
that originally triggered the pandemic.
Since then, a range of dangerous SARS-CoV-2 variants have emerged, including Omicron
, which is currently the most closely watched.
We took a closer look at each new variant of concern and asked if the pocket feature was still there
.
”

Omicron has undergone multiple mutations that allow it to escape the immune protection provided by vaccines or antibody treatments that lag behind this rapidly evolving virus
.
Interestingly, while everything else may have changed, the researchers found that this pocket barely changed, again in Omicron.

Christine Tolzer, a research associate in the School of Biochemistry and lead author of the study, added: "When we realised that the pockets we found had not changed, we looked back and asked if the two deadly coronaviruses, SARS-CoV and MERS-CoV, also contained this linoleic acid binding pocket feature
.
These two coronaviruses triggered previous outbreaks
a few years ago.
”

The team applied high-resolution electron cryomicroscopy, cutting-edge computational methods, and cloud computing
.
Their results show that SARS-CoV and MERS-CoV also have pockets and can bind ligand linoleic acid
through almost the same mechanism.

Professor Schaffitzel concluded: "In our current study, we provide evidence that the pockets of all deadly coronaviruses have remained the same, from the
first SARS coronavirus outbreak 20 years ago to today's omega virus.
We have previously shown that linoleic acid binding to this pocket induces a locked spike that eliminates the infectivity
of the virus.
We have now also shown that linoleic acid supplementation can inhibit the replication of the virus within cells
.
We anticipate that future variants will also contain pockets that we can use to defeat viruses
.
”

Most recently, Professor Schaffitzel co-founded Halo Therapeutics, a branch of the University of Bristol, which is using the findings to develop pocket-bound pan-coronavirus antivirals
.

The team included experts
from Bristol Unveiling Group, Max Planck Bristol Minimal Biocentre, University of Bristol spun Halo Therapeutics Ltd and Swedish and French collaborators.
The research was supported by funding from Max Planck Gesellschaft, the Wellcome Trust and the European Research Council, with additional support
from Oracle's high-performance cloud computing resources study.