COVID-19 caused by SARS-CoV-2 infections has triggered a pandemic massively distorting health care, social and economic life.

New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations.

In the midst of the ongoing COVID-19 outbreak, it is critical to identify new ways to stop the spread of SARS-CoV-2. To that purpose, the Spike (S) protein is of special relevance since it mediates the virus’s major entry mechanism into host cells.

Thus, the interaction of the SARS-CoV-2 S protein with the angiotensin converting enzyme 2 (ACE2) of host cells affects the virus’s infectivity. The inclusion of a camouflage mechanism is required due to the relevance of the S protein in the virus’s survival and spread.

As a result, the virus employs glycosylation as a cloaking technique to build a sugar coat at certain locations of the Spike protein in order to avoid detection by the host’s immune system.

Spotting the wolf by its sheep’s clothing

The explanation may appear straightforward at first glance, but one clear question instantly emerged in the team led by IMBA group head Josef Penninger, who is also the director of the Life Sciences Institute at the University of British Columbia (UBC) in Vancouver, Canada. Specifically, what about lectins, or sugar-binding proteins?

“We intuitively thought that the lectins could help us find new interaction partners of the sugar-coated Spike protein,” says co-first author David Hoffmann, a former PhD student in the Penninger lab at IMBA.

The appeal of this subject stems from how exact it is: the glycosylation locations of the SARS-CoV-2 Spike protein are substantially conserved among circulating variants. By discovering lectins that bind to these glycosylation sites, the researchers may be well on their way to designing effective therapeutic approaches.

In fact, the researchers created and evaluated a library of over 140 mammalian lectins. Clec4g and CD209c were discovered to strongly bind to the SARS-CoV-2 S protein.

“We now have tools at hand that can bind the virus’ protective layer and thereby block the virus from entering cells,” summarizes Stefan Mereiter, co-first author and postdoctoral researcher in the Penninger lab. Mereiter then exclaims: “This mechanism could indeed be the Achilles’ heel scientists have been longing to find!”

The path from Severe acute respiratory CoV-2’s shield” or “sheep’s clothing” to its Achilles’ heel required multiple cutting-edge research methodologies. The researchers worked with Peter Hinterdorfer of the Institute of Biophysics at the University of Linz, Austria, to apply high-tech biophysical approaches to examine the lectin binding process in detail. The researchers, for example, examined which binding forces and how many links exist between the lectins and the Spike protein. This also revealed which sugar structures Clec4g and CD209c bind to.

Therapeutic interventions on the horizon

More good news: the researchers discovered that the two lectins attach to the Spike protein’s N-glycan location N343. This particular location is so important to the Spike that it must never be lost in any infectious variation. In fact, removing this glycosylation site causes the Spike protein to become unstable. Furthermore, several researchers have demonstrated that viruses with altered N343 were non-infectious.

“This means, that our lectins bind to a glycan site that is essential for Spike function – it is therefore very unlikely that a mutant could ever arise that lacks this glycan,” explains Mereiter.

And the storey doesn’t end here. To the surprise of the researchers, the two lectins also reduced SARS-CoV-2 infectivity in human lung cells. These findings, according to Josef Penninger and his colleagues, show promise for pan-variant treatment strategies against SARS-CoV-2.

Penninger sums up: “The approach compares to the mechanism of the drug candidate ‘APN01’ [Apeiron Biologics], which is undergoing advanced clinical trials. This is a bioengineered human ACE2 that also binds to the Spike protein. When the Spike protein is occupied by the drug, the gateway into the cell is blocked. Now, we identified naturally occurring, mammalian lectins that are capable of doing just that!”

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