Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Publication date: Available online 26 May 2018Source: Pharmacology & TherapeuticsAuthor(s): Brice Korkmaz, George H. Caughey, Iain Chapple, Francis Gauthier, Josefine Hirschfeld, Dieter E. Jenne, Ralph Kettritz, Gilles Lalmanach, Anne-Sophie Lamort, Conni Lauritzen, Monika Łȩgowska, Adam Lesner, Sylvain Marchand-Adam, Sarah J. McKaig, Celia Moss, John Pedersen, Helen Roberts, Adrian Schreiber, Seda Seren, Nalin S. ThakkerAbstractCathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects mediated by these proteases in inflammatory/auto-immune disorders. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome (PLS). The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blo...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research