Starting point for antidotes: For the first time, researchers have decoded the structure of the binding protein with which the new coronavirus docks onto human cells. The atomic 3D structure and experiments reveal that this spike protein is very similar to that of the SARS and MERS pathogens, but reacts differently. This knowledge could now facilitate the development of vaccines and antivirals against SARS-CoV-2.
The new corona virus SARS-CoV-2 has not only made the leap from animal to human, it can also skip relatively easily from person to person. Doctors estimate that the virus is about as contagious as the flu. Because the pathogen does not always cause symptoms and can be transmitted during the incubation period, it is difficult to contain the epidemic. Researchers worldwide are therefore working flat out to find vaccines and antivirals for the virus.
Targeting docking protein
An important starting point for such antidotes is a certain surface protein of the coronavirus. With it, it docks onto a receptor on human cells and can thus penetrate them. “Coronavirus spike glycoprotein is a key target for the much needed vaccines, therapeutic antibodies and diagnostics,” said Daniel Wrapp of the University of Texas at Austin and his colleagues.
For docking to work, the corona virus changes the conformation of its spike protein. It opens up and brings itself into a shape that is suitable for the cell receptor. The problem, however, is that this conformation is unstable and therefore cannot be easily mapped or structurally analyzed. To circumvent this, the researchers inserted a mutation in the genetic blueprint for this viral protein that exchanges an amino acid. This change makes the spike protein more stable.
“We knew exactly which mutations we had to use because we had tried this with a number of other corona viruses,” explains senior author Jason McLellan from the University of Texas. This made it possible to image the spike protein of SARS-CoV-2 using cryo-electron microscopy.
More committed than SARS
The images show the part of the protein that is important for binding to the cell in three dimensions and with atomic resolution – both in the inactive and in the bindable active conformation. The 3D structure reveals that this protein hardly differs externally from those of the closely related SARS and MERS pathogens. “We were also able to observe how the spike subunits performed the opening movement,” the researchers report. “This indicates that it has the same trigger mechanism as other corona viruses.”
The decisive difference, however: The new corona virus is apparently better adapted to the human cell than its predecessors. “Surprisingly, the ACE2 receptor binds to the spike binding site of the new corona virus with a ten to 20-fold higher affinity than with SARS-CoV,” said the researchers. “That could explain why this virus spreads so easily from person to person.”
Old antidotes don’t work
And something else is different with the new corona virus: Additional experiments revealed that its spike protein does not respond to existing antibodies against the two related virus types SARS-CoV and Mers-CoV. “In tests with three monoclonal antibodies against Sars, no binding to the spike protein of Sars-CoV-2 could be detected,” the researchers report. The attempt to use the antidotes produced for the SARS epidemic against the new coronavirus would therefore probably make little sense.
The new findings are all the more important: “Knowledge of the atomic structure of the spike protein can now make the design of vaccines and antivirals more precise and facilitate the development of medical countermeasures,” concludes Wrapp and his colleagues. (Science, doi:)
Source: University of Texas at Austin