As with many other viruses, the proteins on the surface of Sars-CoV-2 are not naked – they carry attached sugar molecules that camouflage the coronavirus from the immune system. Researchers have now identified two molecules that bind to this sugar shell around the viral spike protein. As a result, they prevent the virus from entering human cells and thus prevent infection. These active ingredients thus offer a new way of fighting corona infection, as the team explains. It is also positive that the docking points of the two sugar-binding molecules are in a part of the viral protein that is not affected by mutations. The remedies therefore also work against variants.
So far, there are hardly any effective means of combating the Sars-CoV-2 coronavirus after infection. One approach that experimental antibody preparations use, among other things, is the virus’ spike protein. This protruding, prickly protein carries the binding site with which the coronavirus docks and penetrates our cells. If this binding site can be blocked, this could prevent cell entry and thus neutralize the virus. The problem, however: Like many viruses, Sars-CoV-2 also camouflages its spike protein with a kind of camouflage coating made of sugar molecules. These sugars, so-called glycans, attach to the characteristic ends of the protein and thus hide them from the immune system. Because these sugar coatings are also similar to those of the body’s own proteins, the recognition of the virus as foreign is made even more difficult.
Sugar-binding molecules as defense agents
David Hoffmann from the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna and his colleagues have now started with this sugar camouflage for the coronavirus. You have been looking for molecules that can dock onto the sugar structures of Sars-CoV-2 and thereby hinder the virus. As the most promising candidates, the researchers tested more than 140 different lectins – sugar-binding proteins that occur in many different forms in many mammals. “We intuitively thought that the lectins could help us to find new interaction partners for the spike protein,” says Hoffmann. Using high-tech biophysical methods, the team tested which lectins bind to the sugar structures of the viral spike protein and how strongly. Two molecules, the lectins Clec4g and CD209c, turned out to be suitable candidates.
More detailed tests showed that the two lectins bind to the so-called N-glycan site N343 of the spike protein. This specific structure is critical to the stability of the entire spike protein and plays an important role in successful infection, as previous studies have shown. Accordingly, mutations in this structure mean that the coronavirus is no longer infectious. This is one of the reasons why this part of the glycoprotein is unchanged in all virus variants. “This means that our lectins bind to a glycan site that is essential for Spike to function – it is therefore very unlikely that a mutant could ever develop that lacks this glycan,” explains co-first author Stefan Mereiter from the IMBA.
Blocked infection
To find out whether the two lectins can prevent the coronavirus from infecting human cells, the scientists carried out tests with human lung cells. These showed that both lectins attached to the spike protein in such a way that it could no longer dock on the cell surface. Even in the presence of the ACE2 receptor on the cell surface, the lectins retained their blocking binding. As a result, the lung cell infestation decreased significantly, as the team reports. According to Hoffmann and his colleagues, these results show that the sugar coating of Sars-CoV-2 could be a promising starting point for antidotes – and that the lectins could be good candidates for such a therapeutic intervention.
“We now have tools in hand that bind the protective layer of the virus and thus prevent the virus from penetrating cells,” summarizes Mereiter. “This mechanism could indeed be the Achilles’ heel that science has long been hoping to find.”
Source: David Hoffmann (IMBA – Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna) et al., EMBO Journal, doi: 10.15252 / embj.2021108375