9 results on '"Korkmaz, Brice"'
Search Results
2. Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis
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Seren, Seda, Rashed Abouzaid, Maha, Eulenberg-Gustavus, Claudia, Hirschfeld, Josefine, Nasr Soliman, Hala, Jerke, Uwe, N'Guessan, Koffi, Dallet-Choisy, Sandrine, Lesner, Adam, Lauritzen, Conni, Schacher, Beate, Eickholz, Peter, Nagy, Nikoletta, Szell, Marta, Croix, Cécile, Viaud-Massuard, Marie-Claude, Al Farraj Aldosari, Abdullah, Ragunatha, Shivanna, Ibrahim Mostafa, Mostafa, Giampieri, Francesca, Battino, Maurizio, Cornillier, Hélène, Lorette, Gérard, Stephan, Jean-Louis, Goizet, Cyril, Pedersen, John, Gauthier, Francis, Jenne, Dieter E., Marchand-Adam, Sylvain, Chapple, Iain L., Kettritz, Ralph, Korkmaz, Brice, Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Research Center, Helmholtz-Gemeinschaft = Helmholtz Association, University of Birmingham, Medical & Molecular Genetics, University of Birmingham, School of Clinical and Experimental Medicine, Faculty of Chemistry, Technion - Israel Institute of Technology [Haifa], Unizyme Laboratories A/S, Partenaires INRAE, Department of Periodontology, People's Liberation Army No. 309 Hospital, Department of Medical Genetics, University Hospital of North-Norway, Centre National de la Recherche Scientifique (CNRS), King Saud University [Riyadh] (KSU), Department of Dermatology, Venereology, and Leprosy, Sri Siddhartha Medical College, Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Service de dermatologie, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), German Centre for Lung Research, Max Planck Institute of Neurobiology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Ministère de l'Enseignement Supérieur et de la Recherche, the 'Région Centre-Val de Loire' (Project BPCO-Lyse), European Project: 668036,H2020,H2020-PHC-2015-two-stage,RELENT(2015), ProdInra, Migration, RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities - RELENT - - H20202015-11-01 - 2020-04-30 - 668036 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
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Adult ,Male ,neutrophile ,Adolescent ,Neutrophils ,cathepsin C ,Myeloblastin ,Papillon-Lefèvre syndrome ,Médecine humaine et pathologie ,cathepsine ,autoimmune disease ,Cysteine Proteinase Inhibitors ,activation cellulaire ,protease inhibitor ,Young Adult ,antigen ,genetic disease ,cellule souche ,Humans ,cardiovascular diseases ,Child ,hématopoïèse ,aminopeptidase ,granulomatosis with polyangiitis ,neutrophil ,protease ,proteinase 3 ,maladie autoimmune ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Cell Membrane ,inhibiteur pharmacologique ,Case-Control Studies ,Child, Preschool ,Proteolysis ,Enzymology ,Female ,Human health and pathology ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.
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- 2018
3. Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.
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Korkmaz, Brice, Lesner, Adam, Wysocka, Magdalena, Gieldon, Artur, Håkansson, Maria, Gauthier, Francis, Logan, Derek T., Jenne, Dieter E., Lauritzen, Conni, and Pedersen, John
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ELASTASES , *BONE marrow cells , *CYCLOPROPYL compounds , *BONE marrow , *RHEUMATOID arthritis , *AUTOIMMUNE diseases - Abstract
Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC XPZ-01 ((S)-2-amino-N-((1 R ,2 R)-1-cyano-2-(4′-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC XPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness. [ABSTRACT FROM AUTHOR]
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- 2019
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4. Relevance of the mouse model as a therapeutic approach for neutrophil proteinase 3-associated human diseases.
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Korkmaz, Brice, Jenne, Dieter E., and Gauthier, Francis
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LABORATORY mice , *NEUTROPHILS , *PROTEINASES , *ELASTASES , *PROTEOLYTIC enzymes , *INFLAMMATION , *IMMUNOGLOBULINS - Abstract
Abstract: Proteinase 3 (PR3) is one of the four elastase-related serine proteinases stored in the azurophilic granules of neutrophils. Although it participates in the pro- and anti-inflammatory responses to infection and inflammation it also retains specific functions that make it different from neutrophil elastase in spite of their close structural resemblance. PR3 is involved in the immune response to infection and is the major autoantigen in granulomatosis with polyangiitis (GPA, formerly Wegener disease), an autoimmune systemic vasculitis with granulomas. Thus, PR3 appears to be a relevant therapeutic target in a variety of inflammatory human diseases. Animal models are required for the testing of new drugs that target PR3 specifically but differences between human and rodent neutrophil PR3 expression and substrate specificity have greatly impaired progress in this direction. This may explain that, to date, there is no spontaneous model of vasculitis associated with anti-PR3 antibodies. In this review, we will focus on the structural and functional differences between human and murine PR3, and how these differences may be by-passed in order to develop a relevant animal model. [Copyright &y& Elsevier]
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- 2013
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5. Cathepsin C inhibition as a potential treatment strategy in cancer.
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Korkmaz, Brice, Lamort, Anne-Sophie, Domain, Roxane, Beauvillain, Céline, Gieldon, Artur, Yildirim, Ali Önder, Stathopoulos, Georgios T., Rhimi, Moez, Jenne, Dieter E., and Kettritz, Ralph
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ELASTASES , *DISEASE risk factors , *CARCINOGENESIS , *SERINE proteinases , *PROTEOLYTIC enzymes , *NEUTROPHILS - Abstract
[Display omitted] Epidemiological studies established an association between chronic inflammation and higher risk of cancer. Inhibition of proteolytic enzymes represents a potential treatment strategy for cancer and prevention of cancer metastasis. Cathepsin C (CatC) is a highly conserved lysosomal cysteine dipeptidyl aminopeptidase required for the activation of pro-inflammatory neutrophil serine proteases (NSPs, elastase, proteinase 3, cathepsin G and NSP-4). NSPs are locally released by activated neutrophils in response to pathogens and non-infectious danger signals. Activated neutrophils also release neutrophil extracellular traps (NETs) that are decorated with several neutrophil proteins, including NSPs. NSPs are not only NETs constituents but also play a role in NET formation and release. Although immune cells harbor large amounts of CatC, additional cell sources for this protease exists. Upregulation of CatC expression was observed in different tissues during carcinogenesis and correlated with metastasis and poor patient survival. Recent mechanistic studies indicated an important interaction of tumor-associated CatC, NSPs, and NETs in cancer development and metastasis and suggested CatC as a therapeutic target in a several cancer types. Cancer cell-derived CatC promotes neutrophil recruitment in the inflammatory tumor microenvironment. Because the clinical consequences of genetic CatC deficiency in humans resulting in the elimination of NSPs are mild, small molecule inhibitors of CatC are assumed as safe drugs to reduce the NSP burden. Brensocatib, a nitrile CatC inhibitor is currently tested in a phase 3 clinical trial as a novel anti-inflammatory therapy for patients with bronchiectasis. However, recently developed CatC inhibitors possibly have protective effects beyond inflammation. In this review, we describe the pathophysiological function of CatC and discuss molecular mechanisms substantiating pharmacological CatC inhibition as a potential strategy for cancer treatment. [ABSTRACT FROM AUTHOR]
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- 2021
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6. A substrate-based approach to convert SerpinB1 into a specific inhibitor of proteinase 3, the Wegener's granulomatosis autoantigen.
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Jégot, Gwenhael, Derache, Chrystelle, Castella, Sandrine, Lahouassa, Hichem, Pitois, Elodie, Jourdan, Marie Lise, Remold-O'Donnell, Eileen, Kellenberger, Christine, Gauthier, Francis, and Korkmaz, Brice
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SERPINS ,PROTEINASES ,GRANULOMATOSIS with polyangiitis ,ANTIGENS ,NEUTROPHILS - Abstract
The physiological and pathological functions of proteinase 3 (PR3) are not well understood due to its close similarity to human neutrophil elastase (HNE) and the lack of a specific inhibitor. Based on structural analysis of the active sites of PR3 and HNE, we generated mutants derived from the polyvalent inhibitor SerpinB1 (monocyte/neutrophil elastase inhibitor) that specifically inhibit PR3 and that differ from wt-SerpinB1 by only 3 or 4 residues in the reactive center loop. The rate constant of association between the best SerpinB1 mutant and PR3 is 1.4 x 10
7 M-1 ⋅ s-1 , which is ~100-fold higher than that observed with wt-SerpinB1 and compares with that of al-protease inhibitor (α1-PI) toward HNE. SerpinB1 (S/ DAR) is cleaved by HNE, but due to differences in rate, inhibition of PR3 by SerpinB1 (S/DAR) is only minimally affected by the presence of HNE even when the latter is in excess. SerpinB1 (S/DAR) inhibits soluble PR3 and also membrane-bound PR3 at the surface of activated neutrophils. Moreover, SerpinB1 (S/DAR) clears induced PR3 from the surface of activated neutrophils. Overall, these specific inhibitors of PR3 will be valuable for defining biological functions of the protease and may prove useful as therapeutics for PR3-related inflammatory diseases, such as Wegener's granulomatosis. [ABSTRACT FROM AUTHOR]- Published
- 2011
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7. Neutrophil elastase, proteinase 3 and cathepsin G: Physicochemical properties, activity and physiopathological functions
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Korkmaz, Brice, Moreau, Thierry, and Gauthier, Francis
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GEL electrophoresis , *ELECTROPHORESIS , *EXTRACELLULAR matrix , *CONNECTIVE tissues - Abstract
Abstract: Polymorphonuclear neutrophils form a primary line of defense against bacterial infections using complementary oxidative and non-oxidative pathways to destroy phagocytized pathogens. The three serine proteases elastase, proteinase 3 and cathepsin G, are major components of the neutrophil primary granules that participate in the non-oxidative pathway of intracellular pathogen destruction. Neutrophil activation and degranulation results in the release of these proteases into the extracellular medium as proteolytically active enzymes, part of them remaining exposed at the cell surface. Extracellular neutrophil serine proteases also help kill bacteria and are involved in the degradation of extracellular matrix components during acute and chronic inflammation. But they are also important as specific regulators of the immune response, controlling cellular signaling through the processing of chemokines, modulating the cytokine network, and activating specific cell surface receptors. Neutrophil serine proteases are also involved in the pathogenicity of a variety of human diseases. This review focuses on the structural and functional properties of these proteases that may explain their specific biological roles, and facilitate their use as molecular targets for new therapeutic strategies. [Copyright &y& Elsevier]
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- 2008
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8. Differences in the substrate binding sites of murine and human proteinase 3 and neutrophil elastase
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Hajjar, Eric, Korkmaz, Brice, and Reuter, Nathalie
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MOLECULAR dynamics , *PROTEOLYTIC enzymes , *BIOCHEMISTRY , *MATHEMATICAL complexes - Abstract
Abstract: Understanding the differences between murine (m) and human (h) proteinase 3 (PR3) and neutrophil elastase (NE) is crucial for the interpretation of in vivo studies of inflammatory processes. We built structural models of mPR3 and mNE and analyzed their surface properties. We performed molecular dynamics (MD) simulations on several enzyme–peptide complexes to investigate their interaction patterns. The analysis of trajectories confirms that murine and human complexes have different interaction patterns with peptidic substrates. We provide a map of the binding sites of the murine proteases and suggest sequence motifs that we predict to be specific for mPR3 or mNE. [Copyright &y& Elsevier]
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- 2007
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9. Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases.
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Guarino, Carla, Hamon, Yveline, Croix, Cécile, Lamort, Anne-Sophie, Dallet-Choisy, Sandrine, Marchand-Adam, Sylvain, Lesner, Adam, Baranek, Thomas, Viaud-Massuard, Marie-Claude, Lauritzen, Conni, Pedersen, John, Heuzé-Vourc'h, Nathalie, Si-Tahar, Mustapha, Fıratlı, Erhan, Jenne, Dieter E., Gauthier, Francis, Horwitz, Marshall S., Borregaard, Niels, and Korkmaz, Brice
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CATHEPSINS , *NEUTROPHILS , *SERINE proteinases , *ZYMOGENS , *GENETIC mutation , *PAPILLON Lefevre syndrome - Abstract
Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of a N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine protease activities and cause Papillon-Lefèvre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome analysis of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. We aimed to experimentally inactivate and lower neutrophil elastase-like proteases by pharmacological blocking of CatC-dependent maturation in cell-based assays and in vivo . Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. We confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. We also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclinical results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacological inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans. [ABSTRACT FROM AUTHOR]
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- 2017
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