SARS-CoV-2 uses two fusion keys to enter host cells

To enter our cells, the Covid-19 virus fuses its surrounding membrane with the membrane of the target cell. This is where the fusion peptides of the spike protein come into play. These regions function as molecular keys that allow the virus to open the door to the target cell and initiate fusion between the two membranes.

Researchers at ITQB NOVA discovered that SARS-CoV-2 does not have just one key, but two: one at the N-terminal end of the spike protein and another in an internal region. "The two keys act together and are necessary to promote membrane fusion during the virus's entry into the cell," explains Carolina Buga, first author of the new study and a researcher at ITQB NOVA.

In the article published in the Journal of Virology, published by the American Society for Microbiology, the team details that the first region initiates contact with the host cell membrane, allowing the second to insert itself deeper and destabilize it to the point of triggering the virus's entry.

We discovered that the virus has a more complex fusion mechanism than expected."

Carolina Buga,  ITQB NOVA

Understanding in detail how a virus manages to enter our cells is important not only for understanding its biology, but also for identifying ways to block it. The study was the result of a collaboration involving computational, biophysical, and virological approaches.

"It was the combination of these different perspectives that allowed us to identify the two peptides and demonstrate the role they play in membrane fusion," explains Diana Lousa, researcher who led the study. Instituto de Tecnologia Química e Biológica António Xavier of NOVA University Lisbon (ITQB NOVA) joined forces with the Faculty of Medicine of the University of Lisbon, the Gulbenkian Institute for Molecular Medicine, and the Católica Biomedical Research Center.

The researchers also believe that this fusion model may be common to various coronaviruses that conserve the same peptides, which gives this discovery added significance in the broader context of preparing for and responding to future pandemics.