Preventing SARS-CoV-2 infection by targeting human type II transmembrane serine protease activity

Leduc, Richard | $856,000

Quebec Université de Sherbrooke 2020 CIHR Operating Grant

The SARS-CoV-2 coronavirus causing COVID‑19 has been declared a global emergency by the World Health Organization which has mobilized international scientists to collaborate in order to find therapies to counteract the virus’s effects which can be devastating. The strategies need to be as vast as possible since we do not yet know if vaccines or other antiviral drugs will be efficacious. Our group had previously shown in the context of influenza infection that the human host has cell-surface proteases (called type II transmembrane serine proteases or TTSPs) that the virus requires in order to cleave a viral surface protein called hemagglutinin, itself essential for the virus to gain entry into the cell and further replicate using the host cell machinery. We had shown that small molecules inhibiting the activity of lung epithelial cell proteases were efficacious at significantly reducing influenza virulence demonstrating novel anti-viral properties of the compounds. The situation is similar with the SARS-CoV-2 virus but the protein found on the surface of the virus is different. This protein is called the spike glycoprotein (or S protein) and it requires cleavage by human host cell proteases of the TTSP family for its virulence. Our proposal will test protease inhibitors in models where cells are expressing the S protein and the most potent molecules will then be validated in lung organoids to verify their efficacy at reducing viral propagation. We have put together a team of molecular pharmacologists, chemists and virologist with access to containment level 3 facilities to rapidly assess the potential anti-viral properties of the compounds that we already have on hand. In addition, our team will be supported by Dr. Gary Whittaker, Cornell University, one of the world’s expert in coronavirus biology. We believe that these conditions are very favorable for us to have a quick impact in the field and to deliver novel antiviral compounds for patients with COVID-19.

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