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Journal articles on the topic 'Inhibiteur de cathepsine K'

Author: Grafiati

Published: 4 June 2021

Last updated: 18 February 2022

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1

Chapurlat, Roland. "Les inhibiteurs de la cathepsine K et les anticorps anti-sclérostine. Les prochains traitements de l’ostéoporose ?" Revue du Rhumatisme 83, no. 5 (October 2016): 321–23. http://dx.doi.org/10.1016/j.rhum.2016.07.015.

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2

Keegan, Philip M., Suhaas Anbazhakan, Baolin Kang, Betty S. Pace, and Manu O. Platt. "Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-κB." Biological Chemistry 397, no. 5 (May 1, 2016): 459–68. http://dx.doi.org/10.1515/hsz-2015-0244.

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Abstract Cathepsins K and V are powerful elastases elevated in endothelial cells by tumor necrosis factor-α (TNFα) stimulation and disturbed blood flow both of which contribute to inflammation-mediated arterial remodeling. However, mechanisms behind endothelial cell integration of biochemical and biomechanical cues to regulate cathepsin production are not known. To distinguish these mechanisms, human aortic endothelial cells (HAECs) were stimulated with TNFα and exposed to pro-remodeling or vasoprotective shear stress profiles. TNFα upregulated cathepsin K via JNK/c-jun activation, but vasoprotective shear stress inhibited TNFα-stimulated cathepsin K expression. JNK/c-jun were still phosphorylated, but cathepsin K mRNA levels were significantly reduced to almost null indicating separate biomechanical regulation of cathepsin K by shear stress separate from biochemical stimulation. Treatment with Bay 11-7082, an inhibitor of IκBα phosphorylation, was sufficient to block induction of cathepsin K by both pro-remodeling shear stress and TNFα, implicating NF-κB as the biomechanical regulator, and its protein levels were reduced in HAECs by vasoprotective shear stress. In conclusion, NF-κB and AP-1 activation were necessary to activate cathepsin K expression in endothelial cells, highlighting integration of biochemical and biomechanical stimuli to control cathepsins K and V, powerful elastases implicated for arterial remodeling due to chronic inflammation and disturbed blood flow.

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3

James, Ian E., Robert W. Marquis, Simon M. Blake, Shing Mei Hwang, Catherine J. Gress, Yu Ru, Denise Zembryki, et al. "Potent and Selective Cathepsin L Inhibitors Do Not Inhibit Human Osteoclast Resorptionin Vitro." Journal of Biological Chemistry 276, no. 15 (January 8, 2001): 11507–11. http://dx.doi.org/10.1074/jbc.m010684200.

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Cathepsins K and L are related cysteine proteases that have been proposed to play important roles in osteoclast-mediated bone resorption. To further examine the putative role of cathepsin L in bone resorption, we have evaluated selective and potent inhibitors of human cathepsin L and cathepsin K in anin vitroassay of human osteoclastic resorption and anin situassay of osteoclast cathepsin activity. The potent selective cathepsin L inhibitors (Ki= 0.0099, 0.034, and 0.27 nm) were inactive in both thein situcytochemical assay (IC50> 1 μm) and the osteoclast-mediated bone resorption assay (IC50> 300 nm). Conversely, the cathepsin K selective inhibitor was potently active in both the cytochemical (IC50= 63 nm) and resorption (IC50= 71 nm) assays. A recently reported dipeptide aldehyde with activity against cathepsins L (Ki= 0.052 nm) and K (Ki= 1.57 nm) was also active in both assays (IC50= 110 and 115 nm, respectively) These data confirm that cathepsin K and not cathepsin L is the major protease responsible for human osteoclastic bone resorption.

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4

Coppini, Larissa P., Nilana M. T. Barros, Marcela Oliveira, Izaura Y. Hirata, Marcio F. M. Alves, Thaysa Paschoalin, Diego M. Assis, et al. "Plasminogen hydrolysis by cathepsin S and identification of derived peptides as selective substrate for cathepsin V and cathepsin L inhibitor." Biological Chemistry 391, no. 5 (May 1, 2010): 561–70. http://dx.doi.org/10.1515/bc.2010.049.

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Abstract Plasminogen is a glycoprotein implicated in angiogenesis and fibrin clot degradation associated with the release of angiostatin and plasmin activation, respectively. We have recently reported that cathepsin V, but not cathepsins L, B, and K, can release angiostatin-like fragments from plasminogen. Here, we extended the investigation to cathepsin S which has been implicated in angiogenesis and tumor cell proliferation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of plasminogen hydrolysis by cathepsin S revealed generation of two fragments (60 and 38 kDa). Amino-terminal sequencing indicated that cleavage occurs at the Leu469-Leu470 peptide bond. In contrast to cathepsin V, which possesses antiangiogenic activity, cathepsin S plasminogen cleavage products were not capable of inhibiting angiogenesis on endothelial cells. Moreover, we explored the different selectivities presented by cathepsins V and S towards plasminogen and synthesized fluorescence resonance energy transfer peptides encompassing the hydrolyzed peptide bonds by both enzymes. The peptide Abz-VLFEKKQ-EDDnp (Abz=ortho-aminobenzoic acid; EDDnp= N-[2,4-dinitrophenyl]ethylenediamine), hydrolyzed by cath-epsin V at the Phe-Glu bond, is a selective substrate for the enzyme when compared with cathepsins B, L, and S, whereas Abz-VLFEKKVYLQ-EDDnp is an efficient cathepsin L inhibitor. The demonstrated importance of the S3′-P3′ interaction indicates the significance of the extended subsites for enzyme specificity and affinity.

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5

LECAILLE, Fabien, Enrico WEIDAUER, Maria A. JULIANO, Dieter BRÖMME, and Gilles LALMANACH. "Probing cathepsin K activity with a selective substrate spanning its active site." Biochemical Journal 375, no. 2 (October 15, 2003): 307–12. http://dx.doi.org/10.1042/bj20030468.

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The limited availability of highly selective cathepsin substrates seriously impairs studies designed to monitor individual cathepsin activities in biological samples. Among mammalian cysteine proteases, cathepsin K has a unique preference for a proline residue at P2, the primary determinant of its substrate specificity. Interestingly, congopain from Trypanosoma congolense also accommodates a proline residue in its S2 subsite. Analysis of a congopain model showed that amino acids forming its S2 subsite are identical with those of cathepsin K, except Leu67 which is replaced by a tyrosine residue in cathepsin K. Furthermore, amino acid residues of the congopain S2′ binding pocket, which accepts a proline residue, are strictly identical with those of cathepsin K. Abz-HPGGPQ-EDN2ph [where Abz represents o-aminobenzoic acid and EDN2ph (=EDDnp) represents N-(2,4-dinitrophenyl)-ethylenediamine], a substrate initially developed for trypanosomal enzymes, was efficiently cleaved at the Gly–Gly bond by cathepsin K (kcat/Km=426000 M−1·s−1). On the other hand, Abz-HPGGPQ-EDN2ph was resistant to hydrolysis by cathepsins B, F, H, L, S and V (20 nM enzyme concentration) and the Y67L (Tyr67→Leu)/L205A cathepsin K mutant (20 nM), but still acted as a competitive inhibitor. Taken together, the selectivity of Abz-HPGGPQ-EDN2ph to cathepsin K primarily depends on the S2 and S2′ subsite specificities of cathepsin K and the ionization state of histidine at P3. Whereas Abz-HPGGPQ-EDN2ph was hydrolysed by wild-type mouse fibroblast lysates, its hydrolysis was completely abolished in the cathepsin K-deficient samples, indicating that Abz-HPGGPQ-EDN2ph can be used to monitor selectively cathepsin K activity in physiological fluids and cell lysates.

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6

Scaffa, P. M. C., C. M. P. Vidal, N. Barros, T. F. Gesteira, A. K. Carmona, L. Breschi, D. H. Pashley, et al. "Chlorhexidine Inhibits the Activity of Dental Cysteine Cathepsins." Journal of Dental Research 91, no. 4 (January 19, 2012): 420–25. http://dx.doi.org/10.1177/0022034511435329.

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The co-expression of MMPs and cysteine cathepsins in the human dentin-pulp complex indicates that both classes of enzymes can contribute to the endogenous proteolytic activity of dentin. Chlorhexidine (CHX) is an efficient inhibitor of MMP activity. This study investigated whether CHX could also inhibit cysteine cathepsins present in dentin. The inhibitory profile of CHX on the activity of dentin-extracted and recombinant cysteine cathepsins (B, K, and L) was monitored in fluorogenic substrates. The rate of substrate hydrolysis was spectrofluorimetrically measured, and inhibitory constants were calculated. Molecular docking was performed to predict the binding affinity between CHX and cysteine cathepsins. The results showed that CHX inhibited the proteolytic activity of dentin-extracted cysteine cathepsins in a dose-dependent manner. The proteolytic activity of human recombinant cathepsins was also inhibited by CHX. Molecular docking analysis suggested that CHX strongly interacts with the subsites S2 to S2′ of cysteine cathepsins B, K, and L in a very similar manner. Taken together, these results clearly showed that CHX is a potent inhibitor of the cysteine cathepsins-proteolytic enzymes present in the dentin-pulp complex.

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7

Prunk, Mateja, Milica Perišić Nanut, Tanja Jakoš, Jerica Sabotič, Urban Švajger, and Janko Kos. "Extracellular Cystatin F Is Internalised by Cytotoxic T Lymphocytes and Decreases Their Cytotoxicity." Cancers 12, no. 12 (December 6, 2020): 3660. http://dx.doi.org/10.3390/cancers12123660.

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Cystatin F is a protein inhibitor of cysteine cathepsins, peptidases involved in the activation of the effector molecules of the perforin/granzyme pathway. Cystatin F was previously shown to regulate natural killer cell cytotoxicity. Here, we show that extracellular cystatin F has a role in regulating the killing efficiency of cytotoxic T lymphocytes (CTLs). Extracellular cystatin F was internalised into TALL-104 cells, a cytotoxic T cell line, and decreased their cathepsin C and H activity. Correspondingly, granzyme A and B activity was also decreased and, most importantly, the killing efficiency of TALL-104 cells as well as primary human CTLs was reduced. The N-terminally truncated form of cystatin F, which can directly inhibit cathepsin C (unlike the full-length form), was more effective than the full-length inhibitor. Furthermore, cystatin F decreased cathepsin L activity, which, however, did not affect perforin processing. Cystatin F derived from K-562 target cells could also decrease the cytotoxicity of TALL-104 cells. These results clearly show that, by inhibiting cysteine cathepsin proteolytic activity, extracellular cystatin F can decrease the cytotoxicity of CTLs and thus compromise their function.

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8

Altinci, Pinar, Roda Seseogullari-Dirihan, Gulsen Can, David Pashley, and Arzu Tezvergil-Mutluay. "Zinc Inhibits Collagenolysis by Cathepsin K and Matrix Metalloproteinases in Demineralized Dentin Matrix." Caries Research 51, no. 6 (2017): 576–81. http://dx.doi.org/10.1159/000479896.

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The enzymatic degradation of dentin organic matrix occurs via both the action of matrix metalloproteinases (MMPs) and cysteine cathepsins (CCs). Zinc can prevent collagen hydrolysis by MMPs. However, its effect on the activity of dentin-bound CCs is not known. The aim of this study was to investigate the effect of zinc on matrix-bound cathepsin K and MMP activity in dentin. Completely demineralized dentin beams were divided into test groups (n = 9) and incubated at 37°C in an incubation media (1 mL) containing ZnCl2 of 0.02 (physiological level, control), 0.2, 0.5, 1, 5, 10, 20, 30, or 40 mM. The dry mass changes of the beams were determined, and incubation media were analyzed for cathepsin K- and MMP-specific collagen degradation end products - CTX (C-terminal cross-linked telopeptide of type I collagen) and ICTP (cross-linked carboxy-terminal telopeptide of type I collagen) - at 1, 3, and 7 days of incubation. The mass loss of the beams decreased when the zinc level in the incubation media was ≥5 mM (p < 0.05). The release of liberated collagen degradation telopeptides decreased in accordance with the decrease in the mass loss rates of the beams. Cathepsin K-induced dentin collagen degradation can be strongly inhibited by zinc. Zinc levels of ≥5 mM can be considered as a reliable threshold for the stabilization of dentin matrices.

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9

Herroon, Mackenzie K., Rajgopal Sharma, Erandi Rajagurubandara, Claudia Turro, Jeremy J. Kodanko, and Izabela Podgorski. "Photoactivated inhibition of cathepsin K in a 3D tumor model." Biological Chemistry 397, no. 6 (June 1, 2016): 571–82. http://dx.doi.org/10.1515/hsz-2015-0274.

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Abstract Collagenolytic activity of cathepsin K is important for many physiological and pathological processes including osteoclast-mediated bone degradation, macrophage function and fibroblast-mediated matrix remodeling. Here, we report application of a light-activated inhibitor for controlling activity of cathepsin K in a 3D functional imaging assay. Using prostate carcinoma cell line engineered to overexpress cathepsin K, we demonstrate the utility of the proteolytic assay in living tumor spheroids for the evaluation and quantification of the inhibitor effects on cathepsin K-mediated collagen I degradation. Importantly, we also show that utilizing the ruthenium-caged version of a potent nitrile cathepsin K inhibitor (4), cis-[Ru(bpy)2(4)2](BF4)2 (5), offers significant advantage in terms of effective concentration of the inhibitor and especially its light-activated control in the 3D assay. Our results suggest that light activation provides a suitable, attractive approach for spatial and temporal control of proteolytic activity, which remains a critical, unmet need in treatment of human diseases, especially cancer.

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10

Roy, A., F. Gosselin, P. O’Shea, and C.-y. Chen. "Synthesis of a Cathepsin K Inhibitor." Synfacts 2006, no. 11 (November 2006): 1095. http://dx.doi.org/10.1055/s-2006-949394.

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11

Balachandran, Kartik, Philippe Sucosky, Hanjoong Jo, and Ajit P. Yoganathan. "Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 3 (March 2009): H756—H764. http://dx.doi.org/10.1152/ajpheart.00900.2008.

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Matrix metalloproteinases (MMPs) and cathepsins are proteolytic enzymes that are upregulated in diseased aortic valve cusps. The objective of this study was to investigate whether elevated cyclic stretch causes an increased expression and activity of these proteolytic enzymes in the valve cusp. Circumferentially oriented fresh porcine aortic valve cusp sections were stretched to 10% (physiological), 15% (pathological), and 20% (hyperpathological) in a tensile stretch bioreactor for 24 and 48 h. The expression and activity of MMP-1, MMP-2, MMP-9, tissue inhibitor of MMP-1, and cathepsin L, S, and K were quantified and compared with fresh controls. Cell proliferation and apoptosis were also analyzed. As a result, at 10% physiological stretch, the expression and activity of remodeling enzymes were comparable with fresh controls. At 15% stretch, the expression of MMP-1, -2, -9 and cathepsin S and K were upregulated, whereas the expression of cathepsin L was downregulated compared with controls. A similar trend was observed at 20% stretch, but the magnitudes of upregulation and downregulation of the expression were less than those observed at 15%. In addition, there were significantly higher cell proliferation and apoptosis at 20% stretch compared with those of other treatment groups. In conclusion, elevated mechanical stretch on aortic valve cusps may detrimentally alter the proteolytic enzyme expression and activity in valve cells. This may trigger a cascade of events leading to an accelerated valve degeneration and disease progression.

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12

Yang, Hui, Jasmine Heyer, Hui Zhao, Shengxian Liang, Rui Guo, and Li Zhong. "The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer." Molecules 25, no. 18 (September 10, 2020): 4136. http://dx.doi.org/10.3390/molecules25184136.

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(1) Background: Cathepsin K has been found overexpressed in several malignant tumors. However, there is little information regarding the involvement of Cathepsin K in non-small cell lung cancer (NSCLC). (2) Methods: Cathepsin K expression was tested in human NSCLC cell lines A549 and human embryo lung fibroblast MRC-5 cells using Western blot and immunofluorescence assay. Cathepsin K was transiently overexpressed or knocked down using transfection with a recombinant plasmid and siRNA, respectively, to test the effects on cell proliferation, migration, invasion, and on the mammalian target of rapamycin (mTOR) signaling pathway. (3) Results: Expression of Cathepsin K was increased significantly in A549 cells and diffused within the cytoplasm compared to the MRC-5 cells used as control. Cathepsin K overexpression promoted the proliferation, migration, and invasion of A549 cells, accompanied by mTOR activation. Cathepsin K knockdown reversed the above malignant behavior and inhibited the mTOR signaling activation, suggesting that Cathepsin K may promote the progression of NSCLC by activating the mTOR signaling pathway. (4) Conclusion: Cathepsin K may potentially represent a viable drug target for NSCLC treatment.

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13

Kamolmatyakul, S., W. Chen, S. Yang, Y. Abe, R. Moroi, A. M. Ashique, and Y. P. Li. "IL-1α Stimulates Cathepsin K Expression in Osteoclasts via the Tyrosine Kinase-NF-κB Pathway." Journal of Dental Research 83, no. 10 (October 2004): 791–96. http://dx.doi.org/10.1177/154405910408301011.

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Interleukin-1α (IL-1α) is a powerful activator of osteoclast cells. However, the underlying mechanism for this activation is unknown. In this study, we reveal that IL-1α up-regulates the expression of cathepsin K protein, a key protease in bone resorption, by five-fold. Northern blot analysis and promoter analysis show that this induction occurs at the transcriptional level, in a dose-responsive and time-dependent manner. No increase in expression occurs in the presence of either pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-κB, or Genistein, a protein tyrosine kinase inhibitor, suggesting that IL-1α up-regulation may be via the tyrosine kinase-NF-κB pathway to regulate cathepsin K expression. Antisense oligonucleotides to p65, but not the p50 subunit of NF-κB, suppress the IL-1α-induced expression of cathepsin K. We therefore conclude that IL-1α up-regulates cathepsin K gene expression at the transcription level, and this regulation may be via the tyrosine-kinase-NF-κB pathway.

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14

Wang, Yali, Ruolan Li, Zhihui Zheng, Hong Yi, and Zhuorong Li. "Identification of novel cathepsin K inhibitors using ligand-based virtual screening and structure-based docking." RSC Advances 6, no. 86 (2016): 82961–68. http://dx.doi.org/10.1039/c6ra14251f.

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15

Andrault, Pierre-Marie, Sergey A. Samsonov, Gunther Weber, Laurent Coquet, Kamran Nazmi, Jan G. M. Bolscher, Anne-Christine Lalmanach, et al. "Antimicrobial Peptide LL-37 Is Both a Substrate of Cathepsins S and K and a Selective Inhibitor of Cathepsin L." Biochemistry 54, no. 17 (April 27, 2015): 2785–98. http://dx.doi.org/10.1021/acs.biochem.5b00231.

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16

WACHTER, KERRI. "Investigational Cathepsin K Inhibitor Increased BMD in Older Women." Rheumatology News 5, no. 12 (December 2006): 31. http://dx.doi.org/10.1016/s1541-9800(06)71566-6.

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17

Vincents, Bjarne, Patrik Önnerfjord, Milosz Gruca, Jan Potempa, and Magnus Abrahamson. "Down-regulation of human extracellular cysteine protease inhibitors by the secreted staphylococcal cysteine proteases, staphopain A and B." Biological Chemistry 388, no. 4 (April 1, 2007): 437–46. http://dx.doi.org/10.1515/bc.2007.042.

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Abstract Of seven human cystatins investigated, none inhibited the cysteine proteases staphopain A and B secreted by the human pathogen Staphylococcus aureus. Rather, the extracellular cystatins C, D and E/M were hydrolyzed by both staphopains. Based on MALDI-TOF time-course experiments, staphopain A cleavage of cystatin C and D should be physiologically relevant and occur upon S. aureus infection. Staphopain A hydrolyzed the Gly11 bond of cystatin C and the Ala10 bond of cystatin D with similar K m values of approximately 33 and 32 μM, respectively. Such N-terminal truncation of cystatin C caused >300-fold lower inhibition of papain, cathepsin B, L and K, whereas the cathepsin H activity was compromised by a factor of ca. 10. Similarly, truncation of cystatin D caused alleviated inhibition of all endogenous target enzymes investigated. The normal activity of the cystatins is thus down-regulated, indicating that the bacterial enzymes can cause disturbance of the host protease-inhibitor balance. To illustrate the in vivo consequences, a mixed cystatin C assay showed release of cathepsin B activity in the presence of staphopain A. Results presented for the specificity of staphopains when interacting with cystatins as natural protein substrates could aid in the development of therapeutic agents directed toward these proteolytic virulence factors.

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18

Meh, Primož, Miha Pavšič, Vito Turk, Antonio Baici, and Brigita Lenarčič. "Dual concentration-dependent activity of thyroglobulin type-1 domain of testican: specific inhibitor and substrate of cathepsin L." Biological Chemistry 386, no. 1 (January 1, 2005): 75–83. http://dx.doi.org/10.1515/bc.2005.010.

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Abstract The thyroglobulin type-1 (Tg-1) domain is a protein module that occurs in a variety of secreted and membrane proteins and is recognised as a potent inhibitor of cysteine peptidases. We present here some properties of the Tg-1 domain of human testican, a modularly organised proteoglycan secreted mainly by brain cells, the exact in vivo function of which is not yet clear. The domain was prepared as a recombinant protein in a Pichia pastoris expression system and its activity was demonstrated by specific and selective inhibition of cathepsin L (K i=0.14 nM). Interaction at high enzyme and inhibitor concentrations resulted in degradation of the domain by cathepsin L, which was not observed under conditions used for the determination of kinetic parameters. No inhibitory activity could be detected for cathepsin K, but it exhibited a very similar degradation pattern. Homology modelling provided a good explanation for the different behaviour observed with the two enzymes. Firstly, the steric fit between the interfaces of testican domain and cathepsin L is stabilised by numerous favourable forces, while no such interactions are evident in the complex with cathepsin K, and repulsive interactions even prevent access of the domain to the active site of papain. Secondly, the prolonged first loop of the domain occupies a position near the catalytic cysteine residue in a more substrate-like manner, enabling cleavage of the Gly22-Ala23 bond.

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19

Park, Youmie, Jae Yang Kong, and Heeyeong Cho. "A furanquinone fromPaulownia tomentosastem for a new cathepsin K inhibitor." Phytotherapy Research 23, no. 10 (October 2009): 1485–88. http://dx.doi.org/10.1002/ptr.2716.

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20

Zhu, Lingxin, Yi Tang, Xiao-Yan Li, Evan T. Keller, Jingwen Yang, Jung-Sun Cho, Tamar Y. Feinberg, and Stephen J. Weiss. "Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases." Science Translational Medicine 12, no. 529 (February 5, 2020): eaaw6143. http://dx.doi.org/10.1126/scitranslmed.aaw6143.

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Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K–null mice, as well as cathepsin K–mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K–independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone– or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.

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Pérez-Castrillón, José Luis, Florentino Pinacho, Daniel De Luis, María Lopez-Menendez, and Antonio Dueñas Laita. "Odanacatib, a New Drug for the Treatment of Osteoporosis: Review of the Results in Postmenopausal Women." Journal of Osteoporosis 2010 (2010): 1–5. http://dx.doi.org/10.4061/2010/401581.

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Osteoclasts are specialized cells that initiate the process of bone resorption, which has two phases, dissolution of the mineral component and degradation of the organic matrix, in which cathepsin K plays a key role. Cathepsin K inhibitors, which block the activity of cathepsin on bone resorption lacunae, may be a new therapeutic option in osteoporosis. Odanacatib is a nonpeptidic biaryl inhibitor of cathepsin K. Two studies have evaluated the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study of safety and efficacy. Due to the long half-life of odanacatib and the similar effects of different doses on bone remodeling markers, a weekly dosage was chosen for the phase II trail, with the best results being obtained with a dose of 50 mg. At 36 months, increases in bone mineral density similar to those produced by other powerful antiresorptive drugs (zoledronate and denosumab) were observed but there were differences in the behaviour of bone remodeling markers. Data on fractures from the phase III trial currently in development are required to confirm these possible advantages.

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KAFIENAH, Wa'el, Dieter BRÖMME, David J. BUTTLE, Lisa J. CROUCHER, and Anthony P. HOLLANDER. "Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix." Biochemical Journal 331, no. 3 (May 1, 1998): 727–32. http://dx.doi.org/10.1042/bj3310727.

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Cathepsin K (EC 3.4.22.38) is a recently described enzyme that has been shown to cleave type I collagen in its triple helix. The aim of this study was to determine if it also cleaves type II collagen in the triple helix and to identify the helical cleavage site(s) in types I and II collagens. Soluble human and bovine type II collagen, and rat type I collagen, were incubated with cathepsin K before the reaction was stopped with trans-epoxysuccinyl-l-leucylamido-(4-guanidino)butane (E-64). Analysis by SDS/PAGE of the collagen digests showed that optimal activity of cathepsin K against native type II collagen was between pH 5.0 and 5.5 and against denatured collagen between pH 4.0 and 7.0. The enzyme cleaved telopeptides as well as the α1(II) chains, generating multiple fragments in the range 90–120 kDa. The collagenolytic activity was not due to a contaminating metalloenzyme or serine proteinase as it was not inhibited by 1,10-phenanthroline, EDTA or 3,4-dichloroisocoumarin. Western blotting with anti-peptide antibodies to different regions of the α1(II) chain suggested that cathepsin K cleaved native α1(II) chains in the N-terminal region of the helical domain rather than at the well-defined collagenase cleavage site. This was confirmed by N-terminal sequencing of one of the fragments, revealing cleavage at a Gly-Lys bond, 58 residues from the N-terminus of the helical domain. By using a similar approach, cathepsin K was found to cleave native type I collagen close to the N-terminus of its triple helix. These results indicate that cathepsin K could have a role in the turnover of type II collagen, as well as type I collagen.

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23

Sharma, Vidhu, Preety Panwar, Anthony J. O’Donoghue, Haoran Cui, Rafael V. C. Guido, Charles S. Craik, and Dieter Brömme. "Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor." Biochemical Journal 465, no. 1 (December 12, 2014): 163–73. http://dx.doi.org/10.1042/bj20140809.

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The degradation of extracellular matrix proteins such as elastin and collagen by cathepsin K is selectively regulated by exosites. A specific exosite inhibitor blocks the collagenase and elastase activity without interfering with other proteolytic activities.

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24

Vermeire, Jon, Brian Suzuki, and Conor Caffrey. "Odanacatib, a Cathepsin K Cysteine Protease Inhibitor, Kills Hookworm In Vivo." Pharmaceuticals 9, no. 3 (July 4, 2016): 39. http://dx.doi.org/10.3390/ph9030039.

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25

Conaghan, Philip G., Michael A. Bowes, Sarah R. Kingsbury, Alan Brett, Gwenael Guillard, Biljana Rizoska, Niclas Sjögren, et al. "Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis." Annals of Internal Medicine 172, no. 2 (December 31, 2019): 86. http://dx.doi.org/10.7326/m19-0675.

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26

McGrath, Mary E., Jeffrey L. Klaus, Michael G. Barnes, and Dieter Brömme. "Crystal structure of human cathepsin K complexed with a potent inhibitor." Nature Structural Biology 4, no. 2 (February 1997): 105–9. http://dx.doi.org/10.1038/nsb0297-105.

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27

Kassahun, Kelem, Ian McIntosh, Kenneth Koeplinger, Li Sun, Jennifer E. Talaty, Deborah L. Miller, Russell Dixon, Stefan Zajic, and S. Aubrey Stoch. "Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans." Drug Metabolism and Disposition 42, no. 5 (February 19, 2014): 818–27. http://dx.doi.org/10.1124/dmd.113.056580.

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Isabel, Elise, Kevin P. Bateman, Nathalie Chauret, Wanda Cromlish, Sylvie Desmarais, Le T. Duong, Jean-Pierre Falgueyret, et al. "The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor." Bioorganic & Medicinal Chemistry Letters 20, no. 3 (February 2010): 887–92. http://dx.doi.org/10.1016/j.bmcl.2009.12.083.

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29

Jerome, C., M. Missbach, and R. Gamse. "Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys." Osteoporosis International 22, no. 12 (February 10, 2011): 3001–11. http://dx.doi.org/10.1007/s00198-011-1529-x.

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30

Jerome, C., M. Missbach, and R. Gamse. "Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys." Osteoporosis International 23, no. 1 (March 5, 2011): 339–49. http://dx.doi.org/10.1007/s00198-011-1593-2.

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31

Li, Chun Sing, Denis Deschenes, Sylvie Desmarais, Jean-Pierre Falgueyret, Jacques Yves Gauthier, Donald B. Kimmel, Serge Léger, et al. "Identification of a potent and selective non-basic cathepsin K inhibitor." Bioorganic & Medicinal Chemistry Letters 16, no. 7 (April 2006): 1985–89. http://dx.doi.org/10.1016/j.bmcl.2005.12.071.

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32

Xu, Na, Yuan-Yuan Zhang, Yan Lin, Bin Bao, Lei Zheng, Guo-Ping Shi, and Jian Liu. "Increased levels of lysosomal cysteinyl cathepsins in human varicose veins: A histology study." Thrombosis and Haemostasis 111, no. 02 (2014): 333–44. http://dx.doi.org/10.1160/th13-04-0309.

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SummaryVaricose veins are a major chronic venous disease characterised by extensive remodelling of the extracellular matrix architecture in the vascular wall. Although matrix metalloproteinases have been implicated in these pathologic events, little is known about the functional relevance of other protease family members. Here, we studied the distribution of lysosomal cysteine proteases, cathepsins B, L, K, and S, and their endogenous inhibitor, cystatin C, in long saphenous vein specimens from nine normal donors and 18 patients with varicose veins (VVs). Immunohistochemical analysis demonstrated increased levels of cathepsins L, K, B, and S and reduced levels of cystatin C in VVs. This imbalance between cysteinyl cathepsins and cystatin C may favour VV remodelling. To investigate the inflammatory mechanism of their expression, we examined a detailed inflammatory cell profile in VVs, including macrophages, T lymphocytes, and mast cells. Increased numbers of CD3-positive T cells and tryptase-positive mast cells were found in VVs, and enhanced levels of cysteinyl cathepsins were detected from lesion CD3-positive T cells, chymase-positive mast cells, endothelial cells, and smooth-muscle cells. Elevated cathepsins, and their co-localisation to infiltrated inflammatory cells and to vascular cells, suggest that these proteases participate in extracellular matrix degradation in response to inflammation during VV pathogenesis.

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33

Jiang, Suping, Sean T. Prigge, Lan Wei, Yu-e. Gao, Thomas H. Hudson, Lucia Gerena, John B. Dame, and Dennis E. Kyle. "New Class of Small Nonpeptidyl Compounds BlocksPlasmodium falciparum Development In Vitro by Inhibiting Plasmepsins." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2577–84. http://dx.doi.org/10.1128/aac.45.9.2577-2584.2001.

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ABSTRACT Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins fromPlasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II andP. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a K i of 1 to 6 μM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (K i greater than 280 μM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 μg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, withK i values ranging from 0.05 to 0.68 μM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.

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Desmarais, Sylvie, W. Cameron Black, Renata Oballa, Sonia Lamontagne, Denis Riendeau, Paul Tawa, Le Thi Duong, Maureen Pickarski, and M. David Percival. "Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities." Molecular Pharmacology 73, no. 1 (October 16, 2007): 147–56. http://dx.doi.org/10.1124/mol.107.039511.

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35

Gauthier, Jacques Yves, Nathalie Chauret, Wanda Cromlish, Sylvie Desmarais, Le T. Duong, Jean-Pierre Falgueyret, Donald B. Kimmel, et al. "The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K." Bioorganic & Medicinal Chemistry Letters 18, no. 3 (February 2008): 923–28. http://dx.doi.org/10.1016/j.bmcl.2007.12.047.

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36

Panwar, Preety, Liming Xue, Kent Søe, Kamini Srivastava, Simon Law, Jean-Marie Delaisse, and Dieter Brömme. "An Ectosteric Inhibitor of Cathepsin K Inhibits Bone Resorption in Ovariectomized Mice." Journal of Bone and Mineral Research 32, no. 12 (August 25, 2017): 2415–30. http://dx.doi.org/10.1002/jbmr.3227.

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37

Rohrabaugh, Thomas N., Kelsey A. Collins, Congcong Xue, Jessica K. White, Jeremy J. Kodanko, and Claudia Turro. "New Ru(ii) complex for dual photochemotherapy: release of cathepsin K inhibitor and1O2production." Dalton Transactions 47, no. 34 (2018): 11851–58. http://dx.doi.org/10.1039/c8dt00876k.

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A new Ru(ii) complex releases a cysteine protease inhibitor and produces cytotoxic¹O₂upon irradiation with visible light, making it potentially useful as a dual-action PDT agent.

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38

Le Gall, Céline, Akeila Bellahcène, Edith Bonnelye, Jürg A. Gasser, Vincent Castronovo, Jonathan Green, Johann Zimmermann, and Philippe Clézardin. "A Cathepsin K Inhibitor Reduces Breast Cancer–Induced Osteolysis and Skeletal Tumor Burden." Cancer Research 67, no. 20 (October 15, 2007): 9894–902. http://dx.doi.org/10.1158/0008-5472.can-06-3940.

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Stone, Julie A., Jacqueline B. McCrea, Rose Witter, Stefan Zajic, and S. Aubrey Stoch. "Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis." British Journal of Clinical Pharmacology 85, no. 6 (March 18, 2019): 1072–83. http://dx.doi.org/10.1111/bcp.13869.

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40

Rnger, Thomas M., Silvano Adami, Claude-Laurent Benhamou, Edward Czerwiski, Jordi Farrerons, David L. Kendler, Linda Mindeholm, Giuseppe Realdi, Christian Roux, and Vanessa Smith. "Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib." Journal of the American Academy of Dermatology 66, no. 3 (March 2012): e89-e96. http://dx.doi.org/10.1016/j.jaad.2010.11.033.

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41

Zhuo, Y., J. Y. Gauthier, W. C. Black, M. D. Percival, and L. T. Duong. "Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible." Bone 67 (October 2014): 269–80. http://dx.doi.org/10.1016/j.bone.2014.07.013.

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42

Gu, Yanqing, Weimin Fan, and Guoyong Yin. "The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice." Mediators of Inflammation 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/305071.

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Ginsenoside Rg1 is a natural product extracted fromPanax ginsengC.A. Although Rg1 protects tissue structure and functions by inhibiting local inflammatory reaction, the mechanism remains poorly understood.In vitro, Rg1 dose-dependently inhibited TRAP activity in receptor activator of nuclear factor-κB ligand- (RANKL-) induced osteoclasts and decreased the number of osteoclasts and osteoclast resorption area. Rg1 also significantly inhibited the RANK signaling pathway, including suppressing the expression of Trap, cathepsin K, matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR).In vivo, Rg1 dramatically decreased arthritis scores in CIA mice and effectively controlled symptoms of inflammatory arthritis. Pathologic analysis demonstrated that Rg1 significantly attenuated pathological changes in CIA mice. Pronounced reduction in synovial hyperplasia and inflammatory cell invasion were observed in CIA mice after Rg1 therapy. Alcian blue staining results illustrated that mice treated with Rg1 had significantly reduced destruction in the articular cartilage. TRAP and cathepsin K staining results demonstrated a significant reduction of numbers of OCs in the articular cartilage in proximal interphalangeal joints and ankle joints in Rg1-treated mice. In summary, this study revealed that Rg1 reduced the inflammatory destruction of periarticular bone by inhibiting differentiation and maturation of osteoclasts in CIA mice.

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43

van Acker, Gijs J. D., Ashok K. Saluja, Lakshmi Bhagat, Vijay P. Singh, Albert M. Song, and Michael L. Steer. "Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 3 (September 1, 2002): G794—G800. http://dx.doi.org/10.1152/ajpgi.00363.2001.

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Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, and Steer ML. Gastroenterology 113: 304–310, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in vivo conditions, in two models of pancreatitis by using another highly soluble cell permeant cathepsin B inhibitor,l-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-l-isoleucyl-l-proline methyl ester (CA-074me). Intravenous administration of CA-074me (10 mg/kg) before induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions that inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.

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44

Newman, Zachary L., Stephen H. Leppla, and Mahtab Moayeri. "CA-074Me Protection against Anthrax Lethal Toxin." Infection and Immunity 77, no. 10 (July 27, 2009): 4327–36. http://dx.doi.org/10.1128/iai.00730-09.

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ABSTRACT Anthrax lethal toxin (LT) activates the NLRP1b (NALP1b) inflammasome and caspase-1 in macrophages from certain inbred mouse strains, but the mechanism by which this occurs is poorly understood. We report here that similar to several NLRP3 (NALP3, cryopyrin)-activating stimuli, LT activation of the NLRP1b inflammasome involves lysosomal membrane permeabilization (LMP) and subsequent cytoplasmic cathepsin B activity. CA-074Me, a potent cathepsin B inhibitor, protects LT-sensitive macrophages from cell death and prevents the activation of caspase-1. RNA interference knockdown of cathepsin B expression, however, cannot prevent LT-mediated cell death, suggesting that CA-074Me may also act on other cellular proteases released during LMP. CA-074Me appears to function downstream of LT translocation to the cytosol (as assessed by mitogen-activated protein kinase kinase cleavage), K+ effluxes, and proteasome activity. The initial increase in cytoplasmic activity of cathepsin B occurs at the same time or shortly before caspase-1 activation but precedes a larger-scale lysosomal destabilization correlated closely with cytolysis. We present results suggesting that LMP may be involved in the activation of the NLRP1b inflammasome.

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45

Lupsa, Nikolett, Barbara Érsek, Andor Horváth, András Bencsik, Eszter Lajkó, Pálma Silló, Ádám Oszvald, et al. "Skin‐homing CD8 + T cells preferentially express GPI‐anchored peptidase inhibitor 16, an inhibitor of cathepsin K." European Journal of Immunology 48, no. 12 (November 9, 2018): 1944–57. http://dx.doi.org/10.1002/eji.201847552.

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46

Suzuki, Noriyuki, Koyo Takimoto, and Nobuyuki Kawashima. "Cathepsin K Inhibitor Regulates Inflammation and Bone Destruction in Experimentally Induced Rat Periapical Lesions." Journal of Endodontics 41, no. 9 (September 2015): 1474–79. http://dx.doi.org/10.1016/j.joen.2015.04.013.

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47

Wang, Huan, Hayao Matsuhashi, Brian D. Doan, Steven N. Goodman, Xi Ouyang, and William M. Clark. "Large-scale synthesis of SB-462795, a cathepsin K inhibitor: the RCM-based approaches." Tetrahedron 65, no. 32 (August 2009): 6291–303. http://dx.doi.org/10.1016/j.tet.2009.06.022.

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48

Lee Trout, Robert E., and Robert W. Marquis. "Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K." Tetrahedron Letters 46, no. 16 (April 2005): 2799–801. http://dx.doi.org/10.1016/j.tetlet.2005.02.145.

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49

Kwon, Youngil, Hyunjung Ko, Soojung Kim, and Miri Kim. "The effect of cathepsin K inhibitor surface treatment on delayed tooth replantation in dogs." Dental Traumatology 34, no. 3 (April 26, 2018): 201–7. http://dx.doi.org/10.1111/edt.12397.

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50

Grabowska⁎, U., I. Henderson, M. Edlund, L. Vrang, S. Sedig, Y. Terelius, K. Wikstrom, B. L. Sahlberg, T. Chambers, and E. Lindstrom. "Pharmacological characterization of the potent, selective and orally active cathepsin K inhibitor MIV-711." Bone 50 (May 2012): S164—S165. http://dx.doi.org/10.1016/j.bone.2012.02.515.

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