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Thomas C Hart - One of the best experts on this subject based on the ideXlab platform.
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bioChemiCal and mutational analyses of the Cathepsin C gene CtsC in three north ameriCan families with papillon lefevre syndrome
Human Mutation, 2002Co-Authors: Yuxun Zhang, P S Hart, A J Moretti, O J Bouwsma, E M Fisher, L Dudlicek, Mark J Pettenati, Thomas C HartAbstract:Papillon Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is Caused by mutations in the Cathepsin C gene (CTSC) that maps to Chromosome 11q14. CTSC gene mutations assoCiated with PLS have been Correlated with signifiCantly deCreased enzyme aCtivity. Mutational analysis of the CTSC gene in three North AmeriCan families segregating PLS identified four mutations, inCluding a novel mutation p.G139R. All mutations were assoCiated with dramatiCally reduCed CTSC protease enzyme aCtivity. A homozygous C.96T>G transversion resulting in a p.Y32X Change was present in a MexiCan PLS proband, while one CauCasian PLS proband was a Compound heterozygote for the p.Y32X and p.R272P (C.815G>C) mutations. The other CauCasian PLS proband was a Compound heterozygote for C.415G>A transition and C.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respeCtively. The C.415G>A was not present in more than 300 Controls, suggesting it is not a CTSC polymorphism. BioChemiCal analysis demonstrated almost no deteCtable CTSC aCtivity in leukoCytes of all three probands. These mutations altered restriCtion enzyme sites in the highly Conserved CTSC gene. SequenCe analysis of CTSC exon 3 Confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethniCally diverse populations studied. © 2002 Wiley-Liss, InC.
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evidenCe of a founder effeCt for four Cathepsin C gene mutations in papillon lefevre syndrome patients
Journal of Medical Genetics, 2001Co-Authors: Y Zhang, P S Hart, Erhan Firatli, C Uygur, J J Marks, T Lundgren, Stefan Renvert, D N Tatakis, Michael C Gorry, Thomas C HartAbstract:We desCribe a mutation and haplotype analysis of Papillon-Lefevre syndrome probands that provides evidenCe of a founder effeCt for four separate Cathepsin C mutations. A total of 25 different Cathepsin C mutations have been reported in 32 families with Papillon-Lefevre syndrome (PLS) and assoCiated Conditions. A CharaCteristiC of these findings is the diversity of different Cathepsin C mutations that have been identified. To evaluate the generality of Cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. SequenCe analysis identified two Cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a Common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presenCe of the R272P mutation in probands from these four Saudi families makes this the most frequently reported Cathepsin C mutation. To distinguish between the presenCe of a possible founder effeCt or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval Containing the Cathepsin C gene. Results of haplotype analysis for genetiC polymorphisms within and flanking the Cathepsin C gene are Consistent with inheritanCe of the R272P mutation "identiCal by desCent" from a Common anCestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other Cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritanCe of eaCh of these mutations from Common anCestors. These data suggest that four of the more frequently reported Cathepsin C mutations have been inherited from Common anCestors and provide the first direCt evidenCe for a founder effeCt for Cathepsin C gene mutations in PLS. IdentifiCation of these six short tandem repeat polymorphisms that span the Cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of Cathepsin C mutations in additional PLS families.
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haim munk syndrome and papillon lefevre syndrome are alleliC mutations in Cathepsin C
Journal of Medical Genetics, 2000Co-Authors: Thomas C Hart, P S Hart, Y Zhang, Erhan Firatli, M D Michalec, T E Van Dyke, A Stabholz, A Zlorogorski, Lior Shapira, W A SoskolneAbstract:Of the many palmoplantar keratoderma (PPK) Conditions, only Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are assoCiated with premature periodontal destruCtion. Although both PLS and HMS share the Cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS inCluding araChnodaCtyly, aCroosteolysis, atrophiC Changes of the nails, and a radiographiC deformity of the fingers. While PLS Cases have been identified throughout the world, HMS has only been desCribed among desCendants of a religious isolate originally from CoChin, India. Parental Consanguinity is a CharaCteristiC of many Cases of both Conditions. Although autosomal reCessive transmission of PLS is evident, a more “Complex” autosomal reCessive pattern of inheritanCe with phenotypiC influenCes from a Closely linked modifying loCus has been hypothesised for HMS. ReCently, mutations of the Cathepsin C gene have been identified as the underlying genetiC defeCt in PLS. To determine if a Cathepsin C mutation is also responsible for HMS,we sequenCed the gene in aVeCted and unaVeCted subjeCts from the CoChin isolate in whiCh both the PLS and HMS phenotypes appear. Here we report identifiCation of a mutation of Cathepsin C (exon 6, 2127A→ G) that Changes a highly Conserved amino aCid in the Cathepsin C peptide. This mutation segregates with HMS in four nuClear families.Additionally, the existenCe of a shared Common haplotype for genetiC loCi flanking the Cathepsin C gene suggests that aVeCted subjeCts desCended from the CoChin isolate are homozygous for a mutation inherited “identiCal by desCent” from a Common anCestor. This finding supports simple autosomal reCessive inheritanCe for HMS in these families. We also report a mutation of the same exon 6 CTSC Codon (2126C→T) in a Turkish family with ClassiCal PLS. These findings provide evidenCe that PLS and HMS are alleliC variants of Cathepsin C gene mutations. (J Med Genet 2000;37:88‐94)
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loCalisation of a gene for prepubertal periodontitis to Chromosome 11q14 and identifiCation of a Cathepsin C gene mutation
Journal of Medical Genetics, 2000Co-Authors: Thomas C Hart, P S Hart, M D Michalec, Yingze Zhang, Mary L Marazita, Margaret E Cooper, Othman M Yassin, Mohamad K Nusier, Stephen J WalkerAbstract:Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of young Children that results in destruCtion of the periodontal support of the primary dentition. The Condition may oCCur as part of a reCognised syndrome or may oCCur as an isolated finding. Both autosomal dominant and reCessive forms of Mendelian transmission have been reported for PPP. We report a Consanguineous Jordanian family with four members aVeCted by PPP in two nuClear sibships. The parents of the aVeCted subjeCts are first Cousins. We have loCalised a gene of major eVeCt for PPP in this kindred (Zmax=3.55 for D11S901 at =0.00) to a 14 CM genetiC interval on Chromosome 11q14 flanked by D11S916 and D11S1367. This PPP Candidate interval overlaps the region of Chromosome 11q14 that Contains the Cathepsin C gene responsible for Papillon-Lefevre and Haim-Munk syndromes. SequenCe analysis of the Cathepsin C gene from PPP aVeCted subjeCts from this Jordanian family indiCated that all were homozygous for a missense mutation (1040A→G) that Changes a tyrosine to a Cysteine. All four parents were heterozygous Carriers of this Tyr347Cys Cathepsin C mutation. None of the family members who were heterozygous Carriers for this mutation showed any CliniCal findings of PPP. None of the 50 Controls tested were found to have this Tyr347Cys mutation. This is the first reported gene mutation for nonsyndromiC periodontitis and shows that non-syndromiC PPP is an alleliC variant of the type IV palmoplantar eCtodermal dysplasias. (J Med Genet 2000;37:95‐101)
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Mutations of the Cathepsin C gene are responsible for Papillon-Lefèvre syndrome
Journal of medical genetics, 1999Co-Authors: Thomas C Hart, P. Suzanne Hart, Donald W. Bowden, Michael D Michalec, Scott A. Callison, Steve J Walker, Yingze Zhang, Erhan FiratliAbstract:Papillon-Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and seCondary dentitions. A major gene loCus for PLS has been mapped to a 2.8 CM interval on Chromosome 11q14. Correlation of physiCal and genetiC maps of this interval indiCate it inCludes at least 40 ESTs and six known genes inCluding the lysosomal protease Cathepsin C gene (CTSC). The CTSC message is expressed at high levels in a variety of immune Cells inCluding polymorphonuClear leuCoCytes, maCrophages, and their preCursors. By RT-PCR, we found CTSC is also expressed in epithelial regions Commonly affeCted by PLS, inCluding the palms, soles, knees, and oral keratinised gingiva. The 4.7 kb CTSC gene Consists of two exons. SequenCe analysis of CTSC from subjeCts affeCted with PLS from five Consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C→T) introduCes a premature stop Codon at amino aCid 286. Three exon 2 mutations were identified, inCluding a single nuCleotide deletion (2692delA) of Codon 349 introduCing a frameshift and premature termination Codon, a 2 bp deletion (2673-2674delCT) that results in introduCtion of a stop Codon at amino aCid 343, and a G→A substitution in Codon 429 (2931G→A) introduCing a premature termination Codon. All PLS patients were homozygous for Cathepsin C mutations inherited from a Common anCestor. Parents and sibs heterozygous for Cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis CharaCteristiC of PLS. A more Complete understanding of the funCtional physiology of Cathepsin C Carries signifiCant impliCations for understanding normal and abnormal skin development and periodontal disease susCeptibility. Keywords: Cathepsin C; palmoplantar hyperkeratosis; Papillon-Lefevre syndrome; periodontitis
Conni Lauritzen - One of the best experts on this subject based on the ideXlab platform.
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struCture based design and in vivo anti arthritiC aCtivity evaluation of a potent dipeptidyl CyClopropyl nitrile inhibitor of Cathepsin C
Biochemical Pharmacology, 2019Co-Authors: Brice Korkmaz, Francis Gauthier, Dieter E Jenne, Adam Lesner, Artur Gieldon, Magdalena Wysocka, Maria Hakansson, Derek T Logan, Conni LauritzenAbstract: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, ICatCXPZ-01 ((S)-2-amino-N-((1R,2R)-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 ICatCXPZ-01 aCCumulated in the bone marrow reaChing levels suitable for CatC inhibition. SubCutaneous administration of ICatCXPZ-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.
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therapeutiC targeting of Cathepsin C from pathophysiology to treatment
Pharmacology & Therapeutics, 2018Co-Authors: Brice Korkmaz, George H Caughey, Iain L C Chapple, Francis Gauthier, Josefine Hirschfeld, Dieter E Jenne, Ralph Kettritz, Gilles Lalmanach, Annesophie Lamort, Conni LauritzenAbstract: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-Lefevre 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.
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ConsequenCes of Cathepsin C inaCtivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasCulitis
Journal of Biological Chemistry, 2018Co-Authors: Seda Seren, Josefine Hirschfeld, Adam Lesner, Sandrine Dallet-choisy, Maha Rashed Abouzaid, Claudia Eulenberg-gustavus, Hala Nasr Soliman, Uwe Jerke, Koffi N'guessan, Conni LauritzenAbstract: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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prolonged pharmaCologiCal inhibition of Cathepsin C results in elimination of neutrophil serine proteases
Biochemical Pharmacology, 2017Co-Authors: Carla Guarino, Annesophie Lamort, Adam Lesner, S Marchandadam, Yveline Hamon, Cecile Croix, Sandrine Dalletchoisy, Thomas Baranek, Marieclaude Viaudmassuard, Conni LauritzenAbstract: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-Lefevre 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.
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ACtive ReCombinant Rat Dipeptidyl Aminopeptidase I (Cathepsin C) ProduCed Using the BaCulovirus Expression System
Protein expression and purification, 1998Co-Authors: Conni Lauritzen, John Pedersen, Pia M. Martensen, Just Justesen, Mads Thorup Madsen, Søren W. DahlAbstract:AbstraCt An aCtive form of rat dipeptidyl aminopeptidase I (DPPI, Cathepsin C) was obtained by heterologous expression in inseCt Cells. BaCuloviruses Carrying a CDNA sequenCe enCoding the entire rat DPPI preCursor was used to infeCt High Five Cells in a serum-free medium. ReCombinant DPPI (rDPPI) was seCreted into the medium from whiCh it was purified by a Combination of ammonium sulfate fraCtionation, hydrophobiC interaCtion Chromatography (HIC), and ion-exChange Chromatography. A polyhistidine-tagged form of the enzyme (HT-rDPPI) was purified from the medium by immobilized metal affinity Chromatography (IMAC). In vivo aCtivation of native rat DPPI involves at least three Chain Cleavages per subunit and the ability of the expression system to imitate this proCessing was investigated. Both rDPPI and HT-rDPPI were seCreted into the medium as unproCessed and inaCtive proenzymes and gradually Converted into their aCtive forms in the medium. This proCess was not Completed at the time of harvest but mature enzyme proCessed similarly to native rat and human DPPI Could be obtained by inCubating the eluates from the HIC and IMAC Columns at pH 4.5 and 5°C for 18–40 h. The yield of purified and matured enzyme was approximately 50 mg/liter, and it was shown that rDPPI and HT-rDPPI were aCtive against both a dipeptide– p -nitroanilide substrate and human growth hormone N-terminally extended with an Ala-Glu dipeptide.
P S Hart - One of the best experts on this subject based on the ideXlab platform.
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bioChemiCal and mutational analyses of the Cathepsin C gene CtsC in three north ameriCan families with papillon lefevre syndrome
Human Mutation, 2002Co-Authors: Yuxun Zhang, P S Hart, A J Moretti, O J Bouwsma, E M Fisher, L Dudlicek, Mark J Pettenati, Thomas C HartAbstract:Papillon Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is Caused by mutations in the Cathepsin C gene (CTSC) that maps to Chromosome 11q14. CTSC gene mutations assoCiated with PLS have been Correlated with signifiCantly deCreased enzyme aCtivity. Mutational analysis of the CTSC gene in three North AmeriCan families segregating PLS identified four mutations, inCluding a novel mutation p.G139R. All mutations were assoCiated with dramatiCally reduCed CTSC protease enzyme aCtivity. A homozygous C.96T>G transversion resulting in a p.Y32X Change was present in a MexiCan PLS proband, while one CauCasian PLS proband was a Compound heterozygote for the p.Y32X and p.R272P (C.815G>C) mutations. The other CauCasian PLS proband was a Compound heterozygote for C.415G>A transition and C.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respeCtively. The C.415G>A was not present in more than 300 Controls, suggesting it is not a CTSC polymorphism. BioChemiCal analysis demonstrated almost no deteCtable CTSC aCtivity in leukoCytes of all three probands. These mutations altered restriCtion enzyme sites in the highly Conserved CTSC gene. SequenCe analysis of CTSC exon 3 Confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethniCally diverse populations studied. © 2002 Wiley-Liss, InC.
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evidenCe of a founder effeCt for four Cathepsin C gene mutations in papillon lefevre syndrome patients
Journal of Medical Genetics, 2001Co-Authors: Y Zhang, P S Hart, Erhan Firatli, C Uygur, J J Marks, T Lundgren, Stefan Renvert, D N Tatakis, Michael C Gorry, Thomas C HartAbstract:We desCribe a mutation and haplotype analysis of Papillon-Lefevre syndrome probands that provides evidenCe of a founder effeCt for four separate Cathepsin C mutations. A total of 25 different Cathepsin C mutations have been reported in 32 families with Papillon-Lefevre syndrome (PLS) and assoCiated Conditions. A CharaCteristiC of these findings is the diversity of different Cathepsin C mutations that have been identified. To evaluate the generality of Cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. SequenCe analysis identified two Cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a Common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presenCe of the R272P mutation in probands from these four Saudi families makes this the most frequently reported Cathepsin C mutation. To distinguish between the presenCe of a possible founder effeCt or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval Containing the Cathepsin C gene. Results of haplotype analysis for genetiC polymorphisms within and flanking the Cathepsin C gene are Consistent with inheritanCe of the R272P mutation "identiCal by desCent" from a Common anCestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other Cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritanCe of eaCh of these mutations from Common anCestors. These data suggest that four of the more frequently reported Cathepsin C mutations have been inherited from Common anCestors and provide the first direCt evidenCe for a founder effeCt for Cathepsin C gene mutations in PLS. IdentifiCation of these six short tandem repeat polymorphisms that span the Cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of Cathepsin C mutations in additional PLS families.
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identifiCation of Cathepsin C mutations in ethniCally diverse papillon lefevre syndrome patients
Journal of Medical Genetics, 2000Co-Authors: P S Hart, Y Zhang, Erhan Firatli, C Uygur, M Lotfazar, M D Michalec, J J Marks, B J Coates, W K Seow, R I MarshallAbstract:INTRODUCTION Papillon-Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterised by palmoplantar keratoderma and severe, early onset periodontitis, whiCh results from defiCienCy of Cathepsin C aCtivity seCondary to mutations in the Cathepsin C gene. To date, 13 different Cathepsin C mutations have been reported in PLS patients, all of whiCh are homozygous for a given mutation, refleCting Consanguinity. AIM To evaluate the generality of Cathepsin C mutations in PLS, we studied an ethniCally diverse group of 20 unrelated families. METHODS Mutations were identified by direCt automated sequenCing of genomiC DNA amplified for exoniC regions and assoCiated spliCe site junCtions of the Cathepsin C gene. Long range PCR was performed to determine the genomiC struCture of the Cathepsin C gene. RESULTS The Cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affeCted subjeCts from 14 families. Missense mutations were most Common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were Compound heterozygotes. AffeCted subjeCts with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region. CONCLUSION Mutations in the mature region of Cathepsin C were more likely to be assoCiated with the transgressions of the dermatologiCal lesions, although the results were not statistiCally signifiCant. A Comprehensive list of all Cathepsin C mutations desCribed to date, representing 25 mutations from 32 families with PLS and related Conditions, is also presented.
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haim munk syndrome and papillon lefevre syndrome are alleliC mutations in Cathepsin C
Journal of Medical Genetics, 2000Co-Authors: Thomas C Hart, P S Hart, Y Zhang, Erhan Firatli, M D Michalec, T E Van Dyke, A Stabholz, A Zlorogorski, Lior Shapira, W A SoskolneAbstract:Of the many palmoplantar keratoderma (PPK) Conditions, only Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are assoCiated with premature periodontal destruCtion. Although both PLS and HMS share the Cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS inCluding araChnodaCtyly, aCroosteolysis, atrophiC Changes of the nails, and a radiographiC deformity of the fingers. While PLS Cases have been identified throughout the world, HMS has only been desCribed among desCendants of a religious isolate originally from CoChin, India. Parental Consanguinity is a CharaCteristiC of many Cases of both Conditions. Although autosomal reCessive transmission of PLS is evident, a more “Complex” autosomal reCessive pattern of inheritanCe with phenotypiC influenCes from a Closely linked modifying loCus has been hypothesised for HMS. ReCently, mutations of the Cathepsin C gene have been identified as the underlying genetiC defeCt in PLS. To determine if a Cathepsin C mutation is also responsible for HMS,we sequenCed the gene in aVeCted and unaVeCted subjeCts from the CoChin isolate in whiCh both the PLS and HMS phenotypes appear. Here we report identifiCation of a mutation of Cathepsin C (exon 6, 2127A→ G) that Changes a highly Conserved amino aCid in the Cathepsin C peptide. This mutation segregates with HMS in four nuClear families.Additionally, the existenCe of a shared Common haplotype for genetiC loCi flanking the Cathepsin C gene suggests that aVeCted subjeCts desCended from the CoChin isolate are homozygous for a mutation inherited “identiCal by desCent” from a Common anCestor. This finding supports simple autosomal reCessive inheritanCe for HMS in these families. We also report a mutation of the same exon 6 CTSC Codon (2126C→T) in a Turkish family with ClassiCal PLS. These findings provide evidenCe that PLS and HMS are alleliC variants of Cathepsin C gene mutations. (J Med Genet 2000;37:88‐94)
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loCalisation of a gene for prepubertal periodontitis to Chromosome 11q14 and identifiCation of a Cathepsin C gene mutation
Journal of Medical Genetics, 2000Co-Authors: Thomas C Hart, P S Hart, M D Michalec, Yingze Zhang, Mary L Marazita, Margaret E Cooper, Othman M Yassin, Mohamad K Nusier, Stephen J WalkerAbstract:Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of young Children that results in destruCtion of the periodontal support of the primary dentition. The Condition may oCCur as part of a reCognised syndrome or may oCCur as an isolated finding. Both autosomal dominant and reCessive forms of Mendelian transmission have been reported for PPP. We report a Consanguineous Jordanian family with four members aVeCted by PPP in two nuClear sibships. The parents of the aVeCted subjeCts are first Cousins. We have loCalised a gene of major eVeCt for PPP in this kindred (Zmax=3.55 for D11S901 at =0.00) to a 14 CM genetiC interval on Chromosome 11q14 flanked by D11S916 and D11S1367. This PPP Candidate interval overlaps the region of Chromosome 11q14 that Contains the Cathepsin C gene responsible for Papillon-Lefevre and Haim-Munk syndromes. SequenCe analysis of the Cathepsin C gene from PPP aVeCted subjeCts from this Jordanian family indiCated that all were homozygous for a missense mutation (1040A→G) that Changes a tyrosine to a Cysteine. All four parents were heterozygous Carriers of this Tyr347Cys Cathepsin C mutation. None of the family members who were heterozygous Carriers for this mutation showed any CliniCal findings of PPP. None of the 50 Controls tested were found to have this Tyr347Cys mutation. This is the first reported gene mutation for nonsyndromiC periodontitis and shows that non-syndromiC PPP is an alleliC variant of the type IV palmoplantar eCtodermal dysplasias. (J Med Genet 2000;37:95‐101)
Erhan Firatli - One of the best experts on this subject based on the ideXlab platform.
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evidenCe of a founder effeCt for four Cathepsin C gene mutations in papillon lefevre syndrome patients
Journal of Medical Genetics, 2001Co-Authors: Y Zhang, P S Hart, Erhan Firatli, C Uygur, J J Marks, T Lundgren, Stefan Renvert, D N Tatakis, Michael C Gorry, Thomas C HartAbstract:We desCribe a mutation and haplotype analysis of Papillon-Lefevre syndrome probands that provides evidenCe of a founder effeCt for four separate Cathepsin C mutations. A total of 25 different Cathepsin C mutations have been reported in 32 families with Papillon-Lefevre syndrome (PLS) and assoCiated Conditions. A CharaCteristiC of these findings is the diversity of different Cathepsin C mutations that have been identified. To evaluate the generality of Cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. SequenCe analysis identified two Cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a Common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presenCe of the R272P mutation in probands from these four Saudi families makes this the most frequently reported Cathepsin C mutation. To distinguish between the presenCe of a possible founder effeCt or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval Containing the Cathepsin C gene. Results of haplotype analysis for genetiC polymorphisms within and flanking the Cathepsin C gene are Consistent with inheritanCe of the R272P mutation "identiCal by desCent" from a Common anCestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other Cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritanCe of eaCh of these mutations from Common anCestors. These data suggest that four of the more frequently reported Cathepsin C mutations have been inherited from Common anCestors and provide the first direCt evidenCe for a founder effeCt for Cathepsin C gene mutations in PLS. IdentifiCation of these six short tandem repeat polymorphisms that span the Cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of Cathepsin C mutations in additional PLS families.
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identifiCation of Cathepsin C mutations in ethniCally diverse papillon lefevre syndrome patients
Journal of Medical Genetics, 2000Co-Authors: P S Hart, Y Zhang, Erhan Firatli, C Uygur, M Lotfazar, M D Michalec, J J Marks, B J Coates, W K Seow, R I MarshallAbstract:INTRODUCTION Papillon-Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterised by palmoplantar keratoderma and severe, early onset periodontitis, whiCh results from defiCienCy of Cathepsin C aCtivity seCondary to mutations in the Cathepsin C gene. To date, 13 different Cathepsin C mutations have been reported in PLS patients, all of whiCh are homozygous for a given mutation, refleCting Consanguinity. AIM To evaluate the generality of Cathepsin C mutations in PLS, we studied an ethniCally diverse group of 20 unrelated families. METHODS Mutations were identified by direCt automated sequenCing of genomiC DNA amplified for exoniC regions and assoCiated spliCe site junCtions of the Cathepsin C gene. Long range PCR was performed to determine the genomiC struCture of the Cathepsin C gene. RESULTS The Cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affeCted subjeCts from 14 families. Missense mutations were most Common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were Compound heterozygotes. AffeCted subjeCts with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region. CONCLUSION Mutations in the mature region of Cathepsin C were more likely to be assoCiated with the transgressions of the dermatologiCal lesions, although the results were not statistiCally signifiCant. A Comprehensive list of all Cathepsin C mutations desCribed to date, representing 25 mutations from 32 families with PLS and related Conditions, is also presented.
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haim munk syndrome and papillon lefevre syndrome are alleliC mutations in Cathepsin C
Journal of Medical Genetics, 2000Co-Authors: Thomas C Hart, P S Hart, Y Zhang, Erhan Firatli, M D Michalec, T E Van Dyke, A Stabholz, A Zlorogorski, Lior Shapira, W A SoskolneAbstract:Of the many palmoplantar keratoderma (PPK) Conditions, only Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are assoCiated with premature periodontal destruCtion. Although both PLS and HMS share the Cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS inCluding araChnodaCtyly, aCroosteolysis, atrophiC Changes of the nails, and a radiographiC deformity of the fingers. While PLS Cases have been identified throughout the world, HMS has only been desCribed among desCendants of a religious isolate originally from CoChin, India. Parental Consanguinity is a CharaCteristiC of many Cases of both Conditions. Although autosomal reCessive transmission of PLS is evident, a more “Complex” autosomal reCessive pattern of inheritanCe with phenotypiC influenCes from a Closely linked modifying loCus has been hypothesised for HMS. ReCently, mutations of the Cathepsin C gene have been identified as the underlying genetiC defeCt in PLS. To determine if a Cathepsin C mutation is also responsible for HMS,we sequenCed the gene in aVeCted and unaVeCted subjeCts from the CoChin isolate in whiCh both the PLS and HMS phenotypes appear. Here we report identifiCation of a mutation of Cathepsin C (exon 6, 2127A→ G) that Changes a highly Conserved amino aCid in the Cathepsin C peptide. This mutation segregates with HMS in four nuClear families.Additionally, the existenCe of a shared Common haplotype for genetiC loCi flanking the Cathepsin C gene suggests that aVeCted subjeCts desCended from the CoChin isolate are homozygous for a mutation inherited “identiCal by desCent” from a Common anCestor. This finding supports simple autosomal reCessive inheritanCe for HMS in these families. We also report a mutation of the same exon 6 CTSC Codon (2126C→T) in a Turkish family with ClassiCal PLS. These findings provide evidenCe that PLS and HMS are alleliC variants of Cathepsin C gene mutations. (J Med Genet 2000;37:88‐94)
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Mutations of the Cathepsin C gene are responsible for Papillon-Lefèvre syndrome
Journal of medical genetics, 1999Co-Authors: Thomas C Hart, P. Suzanne Hart, Donald W. Bowden, Michael D Michalec, Scott A. Callison, Steve J Walker, Yingze Zhang, Erhan FiratliAbstract:Papillon-Lefevre syndrome (PLS) is an autosomal reCessive disorder CharaCterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and seCondary dentitions. A major gene loCus for PLS has been mapped to a 2.8 CM interval on Chromosome 11q14. Correlation of physiCal and genetiC maps of this interval indiCate it inCludes at least 40 ESTs and six known genes inCluding the lysosomal protease Cathepsin C gene (CTSC). The CTSC message is expressed at high levels in a variety of immune Cells inCluding polymorphonuClear leuCoCytes, maCrophages, and their preCursors. By RT-PCR, we found CTSC is also expressed in epithelial regions Commonly affeCted by PLS, inCluding the palms, soles, knees, and oral keratinised gingiva. The 4.7 kb CTSC gene Consists of two exons. SequenCe analysis of CTSC from subjeCts affeCted with PLS from five Consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C→T) introduCes a premature stop Codon at amino aCid 286. Three exon 2 mutations were identified, inCluding a single nuCleotide deletion (2692delA) of Codon 349 introduCing a frameshift and premature termination Codon, a 2 bp deletion (2673-2674delCT) that results in introduCtion of a stop Codon at amino aCid 343, and a G→A substitution in Codon 429 (2931G→A) introduCing a premature termination Codon. All PLS patients were homozygous for Cathepsin C mutations inherited from a Common anCestor. Parents and sibs heterozygous for Cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis CharaCteristiC of PLS. A more Complete understanding of the funCtional physiology of Cathepsin C Carries signifiCant impliCations for understanding normal and abnormal skin development and periodontal disease susCeptibility. Keywords: Cathepsin C; palmoplantar hyperkeratosis; Papillon-Lefevre syndrome; periodontitis
Dieter E Jenne - One of the best experts on this subject based on the ideXlab platform.
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Cathepsin C inhibition as a potential treatment strategy in CanCer
Biochemical Pharmacology, 2021Co-Authors: Brice Korkmaz, Dieter E Jenne, Annesophie Lamort, Roxane Domain, Celine Beauvillain, Artur Gieldon, A O Yildirim, Georgios T Stathopoulos, Moez RhimiAbstract: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.
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lung proteCtion by Cathepsin C inhibition a new hope for Covid 19 and ards
Journal of Medicinal Chemistry, 2020Co-Authors: Brice Korkmaz, Adam Lesner, S Marchandadam, C Moss, Dieter E JenneAbstract:Cathepsin C (CatC) is a Cysteine dipeptidyl aminopeptidase that aCtivates most of tissue-degrading elastase-related serine proteases. Thus, CatC appears as a potential therapeutiC target to impair protease-driven tissue degradation in ChroniC inflammatory and autoimmune diseases. A depletion of proinflammatory elastase-related proteases in neutrophils is observed in patients with CatC defiCienCy (Papillon-Lefevre syndrome). To address and CounterbalanCe unwanted effeCts of elastase-related proteases, ChemiCal inhibitors of CatC are being evaluated in preCliniCal and CliniCal trials. Neutrophils may Contribute to the diffuse alveolar inflammation seen in aCute respiratory distress syndrome (ARDS) whiCh is Currently a growing Challenge for intensive Care units due to the outbreak of the COVID-19 pandemiC. Elimination of elastase-related neutrophil proteases may reduCe the progression of lung injury in these patients. PharmaCologiCal CatC inhibition Could be a potential therapeutiC strategy to prevent the irreversible pulmonary failure threatening the life of COVID-19 patients.
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premediCation with a Cathepsin C inhibitor alleviates early primary graft dysfunCtion in mouse reCipients after lung transplantation
Scientific Reports, 2019Co-Authors: Salome R T Rehm, John Pedersen, Brice Korkmaz, Dieter E Jenne, A O Yildirim, Natalia F Smirnova, Carmela Morrone, Jessica Gotzfried, Annette FeuchtingerAbstract:Neutrophil serine proteases (NSPs), like proteinase 3 (PR3) and neutrophil elastase (NE) are impliCated in isChemia-reperfusion responses after lung transplantation (LTx). Cathepsin C (CatC) aCts as the key regulator of NSP maturation during biosynthesis. We hypothesized that CatC inhibitors would reduCe vasCular breakdown and inflammation during reperfusion in pretreated lung transplant reCipients by bloCking NSP maturation in the bone marrow. An orthotopiC LTx model in miCe was used to mimiC the induCtion of an isChemia-reperfusion response after 18 h Cold storage of the graft and LTx. ReCipient miCe were treated subCutaneously with a ChemiCal CatC inhibitor (ICatC) for 10 days prior to LTx. We examined the effeCt of the ICatC treatment by measuring the gas exChange funCtion of the left lung graft, protein Content, neutrophil numbers and NSP aCtivities in the bone marrow 4 h after reperfusion. Pre-operative ICatC treatment of the reCipient miCe improved early graft funCtion and lead to the disappearanCe of aCtive NSP protein in the transplanted lung. NSP aCtivities were also substantially reduCed in bone marrow neutrophils. Preemptive NSP reduCtion by CatC inhibition may prove to be a viable and effeCtive approaCh to reduCe immediate isChemia reperfusion responses after LTx.
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struCture based design and in vivo anti arthritiC aCtivity evaluation of a potent dipeptidyl CyClopropyl nitrile inhibitor of Cathepsin C
Biochemical Pharmacology, 2019Co-Authors: Brice Korkmaz, Francis Gauthier, Dieter E Jenne, Adam Lesner, Artur Gieldon, Magdalena Wysocka, Maria Hakansson, Derek T Logan, Conni LauritzenAbstract: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, ICatCXPZ-01 ((S)-2-amino-N-((1R,2R)-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 ICatCXPZ-01 aCCumulated in the bone marrow reaChing levels suitable for CatC inhibition. SubCutaneous administration of ICatCXPZ-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.
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therapeutiC targeting of Cathepsin C from pathophysiology to treatment
Pharmacology & Therapeutics, 2018Co-Authors: Brice Korkmaz, George H Caughey, Iain L C Chapple, Francis Gauthier, Josefine Hirschfeld, Dieter E Jenne, Ralph Kettritz, Gilles Lalmanach, Annesophie Lamort, Conni LauritzenAbstract: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-Lefevre 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.