University of Birmingham Therapeutic targeting of cathepsin C: Korkmaz, Brice; Caughey, George H.; Chapple, Iain; Gauthier, Francis; Hirschfeld, Josefine; Jenne, Dieter E.; Kettritz, Ralph; Lalmanach, Gilles; Lamort, Anne-Sophie; Lauritzen, Conni; gowska, Monika; Lesner, Adam; Marchand-Adam, Sylvain; McKaig, Sarah J.; Moss, Celia; Pedersen, John; Roberts, Helen; Schreiber, Adrian; Seren, Seda; Thakker, Nalin S. DOI: 10.1016/j.pharmthera.2018.05.011 License: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) Document Version Peer reviewed version Citation for published version (Harvard): Korkmaz, B, Caughey, GH, Chapple, I, Gauthier, F, Hirschfeld, J, Jenne, DE, Kettritz, R, Lalmanach, G, Lamort, A-S, Lauritzen, C, gowska, M, Lesner, A, Marchand-Adam, S, McKaig, SJ, Moss, C, Pedersen, J, Roberts, H, Schreiber, A, Seren, S & Thakker, NS 2018, 'Therapeutic targeting of cathepsin C: from pathophysiology to treatment', Pharmacology & Therapeutics, vol. 190, pp. 202-236. https://doi.org/10.1016/j.pharmthera.2018.05.011 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Thakkar PII: S0163-7258(18)30091-3 DOI: doi:10.1016/j.pharmthera.2018.05.011 Reference: JPT 7227 To appear in: Please cite this article as: Brice Korkmaz, George H. Caughey, Iain Chapple, Francis Gauthier, Josefine Hirschfeld, Dieter E. Jenne, Ralph Kettritz, Gilles Lalmanach, Anne- Sophie Lamort, Conni Lauritzen, Monika Legowska, Adam Lesner, Sylvain Marchand- Adam, Sarah J. McKaig, Celia Moss, John Pedersen, Helen Roberts, Adrian Schreiber, Seda Seren, Nalin S. Thakkar , Therapeutic targeting of cathepsin C: from pathophysiology to treatment. (2018), doi:10.1016/j.pharmthera.2018.05.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Therapeutic Targeting of Cathepsin C: from pathophysiology to treatment Brice Korkmaz1*, George H. Caughey2, Iain Chapple3, Francis Gauthier1, Josefine Hirschfeld3, Dieter E. Jenne4, Ralph Kettritz5, Gilles Lalmanach1, Anne-Sophie Lamort4, Conni Lauritzen6 , Monika Legowska7, Adam Lesner7, Sylvain Marchand-Adam1, Sarah J. McKaig8, Celia Moss9, John Pedersen6, Helen Roberts3, Adrian Schreiber5, Seda Seren1, Nalin S. Thakkar10 Authors contributed equally to this work 1INSERM UMR1100, “Centre d’Etude des Pathologies Respiratoires” and Université de Tours, Tours, France 2Department of Medicine, University of California, San Francisco, California, USA 3Institute of Clinical Sciences, College of Medical and Dental Sciences, Periodontal Research Group, University of Birmingham, and Birmingham Community Health Trust, Edgbaston, Birmingham, UK 4Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research, Munich, Germany 5Experimental and Clinical Research Center, a joint cooperation between the Charité and the Max- Delbrück Center for Molecular Medicine and Department of Nephrology and Medical Intensive Care, Charité-Universitaetsmedizin, Berlin, Germany 6Unizyme Laboratories A/S, Hörsholm, Denmark 7Faculty of Chemistry, University of Gdansk, Poland 8Pediatric Dental Surgeon, Birmingham Women’s and Children’s NHS Foundation Trust, University of Birmingham, Birmingham, UK 9Pediatric Dermatology, Birmingham Women’s and Children’s NHS Foundation Trust, University of Birmingham, Birmingham, UK 10Department of Histopathology, Manchester Royal Infirmary, UK Running title: Therapeutic targeting of cathepsin C *Corresponding author:ACCEPTED Brice Korkmaz MANUSCRIPT INSERM UMR1100 “Centre d’Etude des Pathologies Respiratoires (CEPR)”, Université de Tours, Faculté de Médecine 10 Bld. Tonnellé, 37032, Tours, France e-mail: [email protected] Tel: 0033 2 47 36 63 86 ACCEPTED MANUSCRIPT 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. Key words: cathepsin C, serine proteases, Papillon-Lefèvre syndrome, inflammatory/autoimmune diseases, therapeutic inhibitors, pharmacological targeting Abbreviations: AAT, 1-antitrypsin; AATD, 1-antitrypsin deficiency; ANCA, anti-neutrophil cytoplasmic autoantibody;ACCEPTED AAV, ANCA-associated MANUSCRIPT vasculitis; Cat, cathepsin; COPD, chronic obstructive pulmonary disease, GPA, granulomatosis with polyangiitis; HMS, Haim-Munk syndrome; IL, interleukin; MMP, matrix metalloprotease; MPO, myeloperoxidase; NCGN, necrotizing crescengic glomerulonephritis; MPA, microscopic polyangiitis, NE, neutrophil elastase; NETs, neutrophil extracellular traps; NSP, neutrophil serine protease; PLS, Papillon-Lefèvre syndrome; PPK, palmo- ACCEPTED MANUSCRIPT plantar keratoderma; PR3, proteinase 3, mPR3, membrane-bound PR3; MIP1α, macrophage inhibitory protein-1 alpha; ROS, reactive oxygen species. ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT 1. INTRODUCTION Complex type serine proteases of coagulation and clotting system and the simple digestive proteases of the pancreas are synthesized and either constitutively secreted or stored as inactive precursors (zymogens) in cellular granules. In response to specific stimuli, these zymogens are locally and transiently converted to their active forms by strictly regulated limited proteolysis. By contrast, immune defense cells including neutrophils, mast cells, lymphocytes and macrophages, express a unique subset of eleven single domain serine proteases whose zymogens are already constitutively converted to their active form by cathepsin C (CatC) during biosynthesis, sorting and storage in cytoplasmic granules. CatC, also known as dipeptidyl peptidase 1 (DPP1, EC 3.4.14.1), is a ubiquitously expressed lysosomal cysteine exopeptidase belonging to the papain family of cysteine peptidases (Turk, et al., 2001). It was discovered by Gutman and Fruton (Gutmann & Fruton, 1948). CatC cleaves two residues from the N-termini of proteins and peptides and is considered to be a major intracellular processing enzyme. CatC has an essential role in the activation of various granule serine proteases from neutrophils (elastase (NE), cathepsin