Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

  • Biochem Pharmacol. 2024 Nov:229:116114. doi: 10.1016/j.bcp.2024.116114.
Roxane Domain  1 ,  Seda Seren  1 ,  Uwe Jerke  2 ,  Manousos Makridakis  3 ,  Kuan-Ju Chen  4 ,  Jérôme Zoidakis  3 ,  Moez Rhimi  5 ,  Xian Zhang  6 ,  Tillia Bonvent  1 ,  Cécile Croix  1 ,  Loïc Gonzalez  1 ,  Dedong Li  4 ,  Jessica Basso  4 ,  Christophe Paget  1 ,  Marie-Claude Viaud-Massuard  1 ,  Gilles Lalmanach  1 ,  Guo-Ping Shi  7 ,  Ali Aghdassi  8 ,  Antonia Vlahou  3 ,  Patrick P McDonald  4 ,  Isabelle Couillin  9 ,  Rich Williams  10 ,  Ralph Kettritz  11 ,  Brice Korkmaz  12
Affiliations
  • 1. INSERM UMR-1100, Research Center for Respiratory Diseases, Tours, France; Université de Tours, Tours, France.
  • 2. Experimental and Clinical Research Center, Charité und Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC), Berlin, Germany.
  • 3. Biotechnology Division, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • 4. Research Department, Insmed Incorporated, Bridgewater, NJ, USA.
  • 5. INRAE UMR-1319, Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.
  • 6. School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.
  • 7. Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 8. Department of Medicine A - Gastroenterology, Nephrology, Endocrinology and Rheumatology, University Medicine Greifswald, Greifswald, Germany.
  • 9. CNRS UMR-7355, Experimental and Molecular Immunology and Neurogenetics, Université d'Orléans, Orleans, France.
  • 10. The Patrick G Johnston Center for Cancer Research, Queen's University, Belfast, UK.
  • 11. Experimental and Clinical Research Center, Charité und Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC), Berlin, Germany; Nephrology and Intensive Care Medicine, Charité-Universitätsmedizin, Berlin, Germany.
  • 12. INSERM UMR-1100, Research Center for Respiratory Diseases, Tours, France; Université de Tours, Tours, France. Electronic address: [email protected].
PMID: 39455238 DOI: 10.1016/j.bcp.2024.116114
Abstract

An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in theirCTSC gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals), suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34+ progenitor cells were treated with CatS inhibitors during neutrophilic differentiation in vitro, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases.

Keywords
Cathepsin C; Cysteine cathepsin; Neutrophil serine protease; Synthetic inhibitor; Therapeutic approach; Zymogen.
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