The novel coronavirus SARS-CoV-2 is transmitted from animals to humans and has spread worldwide, causing a pandemic lung disease, COVID-19. To date, more than 200,000 people have died from COVID-19.
The virus enters and infects human cells via a “spike protein,” which allows the virus to attach to cells and deliver its genome to the cell, which is necessary for the virus to replicate itself. In the case of SARS-CoV-2, there is an unusual activation sequence of the spike protein. Now, scientists at the Infection Biology Unit of the German Primate Center (DPZ) - Leibniz Institute for Primate Research have discovered that this sequence is split or “cleaved” by a cellular enzyme (protease) called furin. Further, this cleavage is critical for infecting the cells of the lungs. This new research helps define new possibilities for therapy and vaccine research and is published in the journal, Molecular Cell.
The SARS-CoV-2 spike protein carries an activation sequence at the “S1/S2” cleavage site, which is like that of avian influenzas. These similarities have not, however, been found in viruses more closely related to SARS-CoV-2.
Scientists led by Markus Hoffmann and Stefan Pöhlmann of the German Primate Center were able to determine that the S1/S2 activation sequence of the SARS-CoV-2 spike protein is cleaved by furin and this process is essential for the virus to infect the lungs. This critical for infected cells to fuse with uninfected cells. The scientists believe that this mechanism might be how the virus spreads in the body without leaving the host cell.
Says Pöhlmann, “Our results suggest that inhibition of furin should block the spread of SARS-CoV-2 in the lung. Furthermore, our present study and previous work demonstrate that the virus uses a two-step activation mechanism: In infected cells, the spike protein has to be cleaved by the protease furin so that newly formed viruses can then use the protease TMPRSS2 for further cleavage of the spike protein, which is important for the entry into lung cells."
According to Hoffmann, “SARS-CoV-2 variants, in which the activation sequence for furin has been removed, could be used as a basis for the development of such live attenuated vaccines, since the lack of cleavage of the spike protein should greatly limit the spread of the virus in the body. A sufficiently attenuated virus would no longer be able to cause disease but would still enable the immune system to react to the pathogen and, for example, produce neutralizing antibodies.”