TY - JOUR
T1 - Therapeutic targeting of cathepsin C:
T2 - from pathophysiology to treatment
AU - Korkmaz, Brice
AU - Caughey, George H.
AU - Chapple, Iain
AU - Gauthier, Francis
AU - Hirschfeld, Josefine
AU - Jenne, Dieter E.
AU - Kettritz, Ralph
AU - Lalmanach, Gilles
AU - Lamort, Anne-Sophie
AU - Lauritzen, Conni
AU - Łȩgowska, Monika
AU - Lesner, Adam
AU - Marchand-Adam, Sylvain
AU - McKaig, Sarah J.
AU - Moss, Celia
AU - Pedersen, John
AU - Schreiber, Adrian
AU - Seren, Seda
AU - Thakker, Nalin S.
AU - Helen M, Roberts
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Cathepsin 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 blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.
AB - Cathepsin 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 blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.
KW - Cathepsin C
KW - Serine proteases
KW - Elastease
KW - Proteinase 3
KW - Papillon-Lefèvre syndrome
KW - inflammatory/autoimmune diseases
KW - therapeutic inhibitors
KW - pharmacological targeting
U2 - 10.1016/j.pharmthera.2018.05.011
DO - 10.1016/j.pharmthera.2018.05.011
M3 - Article
SN - 0163-7258
VL - 190
SP - 202
EP - 236
JO - Pharmacology & Therapeutics
JF - Pharmacology & Therapeutics
ER -