Multi organ failure is the severe outcome of the coronavirus disease 2019 (COVID-19). Binding of the severe acute respiratory syndrome-related coronavirus 2 spike protein (SARS-CoV-2-S protein) to angiotensinconverting enzyme 2 (ACE2), along with proteolytic digestion of the S protein by transmembrane serine protease 2 (TMPRSS2), provokes the internalization of SARS-CoV-2 into the host cell. Productive infection is due to viral release from the endosome to the cytosol, replication, and cell-to-cell transmission. Strategically infiltrating neutrophils to the site of infection release serine proteases, such as cathepsin G (CatG) and lactoferrin (LF), for immunity. On the downside, uncontrolled CatG activity is responsible for cardiovascular diseases and thrombosis, which are severe complications in COVID-19. In this proposal inhibition of the proteolytic activity of CatG as a plausible treatment is suggested. We will address whether i) Camostat, a clinically proven serine protease inhibitor for chronic pancreatitis, can inhibit CatG in a concentration dependent fashion, ii) CatG/LF can proteolytically digest the SARS-CoV-2-S protein and variant SARS-CoV-2-S protein D614G, iii) the interaction of CatG with the SARS-CoV-2-S protein can enhance host cell entry and whether inhibition of CatG may reduce infection, and iv) natural serine protease inhibitors interfere with the proteolytic activity of TMPRSS2.