Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Brice Korkmaz , George H. Caughey , Iain Chapple , Francis Gauthier , Josefine Hirschfeld , Dieter E. Jenne , Ralph Kettritz , Gilles Lalmanach , Anne-Sophie Lamort , Conni Lauritzen , Monika Łęgowska , Adam Lesner , Sylvain Marchand-Adam , Sarah J. McKaig , Celia Moss , John Pedersen , Helen Roberts , Adrian Schreiber , Seda Seren , Nalin S. Thakkar

Abstract

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 of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. 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.
Publication typeIn press (online first, early view)
Author Brice Korkmaz
Brice Korkmaz,,
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, George H. Caughey
George H. Caughey,,
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, Iain Chapple
Iain Chapple,,
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, Francis Gauthier
Francis Gauthier,,
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, Josefine Hirschfeld
Josefine Hirschfeld,,
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, Dieter E. Jenne
Dieter E. Jenne,,
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, Ralph Kettritz
Ralph Kettritz,,
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, Gilles Lalmanach
Gilles Lalmanach,,
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, Anne-Sophie Lamort
Anne-Sophie Lamort,,
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, Conni Lauritzen
Conni Lauritzen,,
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et al.`
Journal seriesPharmacology & Therapeutics, ISSN 0163-7258
Issue year2018
Volonline first
Pages1-35
Keywords in Englishcathepsin C, serine proteases, Papillon-Lefèvre syndrome, inflammatory/autoimmune diseases, therapeutic inhibitors, pharmacological targeting
DOIDOI:10.1016/j.pharmthera.2018.05.011
URL https://doi.org/10.1016/j.pharmthera.2018.05.011
Languageen angielski
Score (nominal)45
ScoreMinisterial score = 45.0, 19-06-2018, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, 19-06-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 11.127 (2) - 2016=10.011 (5)
Citation count*0 (2018-07-18)
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