Host cysteine protease

Host cysteine proteases are a diverse group of enzymes characterized by a nucleophilic cysteine thiol in their active site, primarily functioning within lysosomes or the extracellular matrix to degrade proteins (Rawlings et al., 2018, MEROPS database). In the context of infectious diseases, these enzymes—most notably Cathepsin L and Cathepsin B—are frequently hijacked by viruses such as SARS-CoV-2, Ebola, and MERS-CoV to facilitate viral entry by cleaving and activating viral spike or envelope glycoproteins (Simmons et al., 2005, PubMed; Hoffmann et al., 2020, Cell). Beyond viral pathogenesis, host cysteine proteases play critical roles in cancer progression by remodeling the extracellular matrix to promote metastasis, and in bone resorption via Cathepsin K (Bromme et al., 1996, PubMed). Therapeutic strategies involve small-molecule inhibitors that target the catalytic triad to block proteolytic activity (Turk et al., 2012, Nature Reviews Drug Discovery). While promising for treating infections and metabolic bone diseases, drug development has faced challenges regarding selectivity and potential side effects related to the essential housekeeping functions of these enzymes in protein turnover and immune signaling (Stoch et al., 2008, Clinical Pharmacology & Therapeutics).

Other names

Thiol proteaseCysteine endopeptidaseLysosomal cysteine proteaseCysteine-type peptidaseCathepsinCathepsin LCathepsin BCathepsin K

Inhibition of the catalytic activity of host-encoded cysteine proteases by binding to the active site, thereby preventing the cleavage of substrate proteins such as viral glycoproteins or extracellular matrix components.