Targeting protease-mediated activation of SARS-CoV-2

discovery - Here, I propose to decipher the role of furin and related proteases in the activation of SARS-CoV-2 spike proteins. We will compare evolutionarily diverse coronaviruses to characterize proteolytic spike maturation and the downstream effects on viral infectivity. Taking advantage of our long-standing expertise in host-virus co-evolution, we will also characterize spike mutations that emerge during the current SARS-CoV-2 pandemic and may confer a selection advantage to the virus as they enhance furin-mediated cleavage. Notably, we previously identified a novel mechanism of antiviral immunity, demonstrating that guanylate-binding proteins 2 and 5 (GBP2/5) restrict a variety of viruses by targeting furin. We hypothesize that this mechanism also suppresses replication of SARS-CoV-2. In a translational approach, we will therefore test whether induction of GBP2/5 and/or inhibition of furin can limit the spread of SARS-CoV 2. The proposed project will not only provide important insights into the determinants of SARS-CoV-2 infectivity and tropism, but also help to assess consequences of mutations emerging during the current outbreak and might identify promising targets for therapeutic intervention.