Proteases modulate SARS-CoV-2 spike protein activation and deactivation Proteases are enzymes that catalyze the break-down of proteins by hydrolysis and are key to the infection process of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike protein that initially interacts with the ACE2 receptor on the surface of host cells must undergo cleavage to initiate a conformational change that allows entry into the cell. Proteolysis can be facilitated, and has been identified to take place, at several stages: by membrane-bound proteases belonging to the host cell, such as TMPRSS2; extracellular proteases, such as furin; or within an endosome following endocytosis by cathepsins B and L, allowing the virus to escape into the cytoplasm.