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Cathepsin k inhibitors

Matthew Huisman, Jessica K White, Veronica G Lewalski, Izabela Podgorski, Claudia Turro, Jeremy J Kodanko
Photochemical control over irreversible inhibition was shown using Ru(ii)-caged inhibitors of cathepsin L. Levels of control were dependent on where the Ru(ii) complex was attached to the organic inhibitor, reaching >10 : 1 with optimal placement. A new strategy for photoreleasing Ru(ii) fragments from inhibitor-enzyme conjugates is also reported.
October 18, 2016: Chemical Communications: Chem Comm
Youshan Li, Huawei Liu, Rui Zhu, Qingyou Xia, Ping Zhao
Previous studies have indicated that most trypsin inhibitor-like cysteine-rich domain (TIL)-type protease inhibitors, which contain a single TIL domain with ten conserved cysteines, inhibit cathepsin, trypsin, chymotrypsin, or elastase. Our recent findings suggest that Cys(2nd) and Cys(6th) were lost from the TIL domain of the fungal-resistance factors in Bombyx mori, BmSPI38 and BmSPI39, which inhibit microbial proteases and the germination of Beauveria bassiana conidia. To reveal the significance of these two missing cysteines in relation to the structure and function of TIL-type protease inhibitors in B...
September 24, 2016: Peptides
Zhen Tan, Jianwen Cheng, Qian Liu, Lin Zhou, Jacob Kenny, Tao Wang, Xixi Lin, Jinbo Yuan, Julian M W Quinn, Jennifer Tickner, Guoju Hong, An Qin, Jinmin Zhao, Jiake Xu
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K...
September 21, 2016: Molecular and Cellular Endocrinology
Le T Duong, Randy Crawford, Kevin Scott, Christopher T Winkelmann, Gouxin Wu, Pete Szczerba, Michael A Gentile
Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7...
September 15, 2016: Bone
Donna Lee M Dinnes, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mi-Jurng Kim, Liming Hou, Wendy Jessup, Kerry-Anne Rye, Morten Thaysen-Andersen, Stuart J Cordwell, Leonard Kritharides
Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I such as chlorination, nitration, oxidation, and proteolysis can impair its antiatherogenic function, although it is unknown if macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDM) were incubated with human apoA-I under conditions used to induce cholesterol export...
September 14, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rui Xing, Yingjian Zhang, Changhong Li, Lin Sun, Lin Yang, Jinxia Zhao, Xiangyuan Liu
Cytokines play a key role in the bone destruction of rheumatoid arthritis (RA). Interleukin-21 (IL-21) promotes osteoclastogenesis in RA in a receptor activator of nuclear factor-κB ligand (RANKL)-dependent way. Whether IL-21 is capable of promoting osteoclastogenesis directly in the absence of RANKL remains unknown. In the present study, we examined the osteoclastogenic activity of IL-21 in RAW264.7 cells in the absence of RANKL. We found that IL-21 enhanced osteoclastogenesis and this was demonstrated by increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive stained, multinucleated cells compared with the negative control...
October 2016: International Journal of Molecular Medicine
Catera L Wilder, Charlene Walton, Valencia Watson, Fermin A A Stewart, Jade Johnson, Shelly R Peyton, Christine K Payne, Valerie Odero-Marah, Manu O Platt
Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors...
October 2016: International Journal of Biochemistry & Cell Biology
Song-Yan Hu, Xiao-Dong Jin, Hao Zhang, Jun Chen, Guo-Zhu Yang, Xiao-Dong Wang, Lu Tang, Xing-Yan Lu, Li Lu, Qing-Nan Li
OBJECTIVE: To explore the role of epithelial sodium channel (ENaC) in regulating the functional activity of osteoclasts. METHODS: Multinucleated osteoclasts were obtained by inducing the differentiation of rat bone marrow cells with macrophage colony-stimulating factor (M-CSF) and RANKL. The osteoclasts were exposed to different concentrations of the ENaC inhibitor amiloride, and the expression of ENaC on osteoclasts was examined using immunofluorescence technique...
August 20, 2016: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Anna Cline-Smith, Jesse Gibbs, Elena Shashkova, Zachary S Buchwald, Deborah V Novack, Rajeev Aurora
A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3(+)CD25(+) regulatory CD8(+) T cells (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG...
August 18, 2016: JCI Insight
Christopher K Y Chan, Alice Mason, Cyrus Cooper, Elaine Dennison
INTRODUCTION: Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population, its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualize the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies-in the form of combinations and altered durations of existing treatments, as well as newer drug therapies...
September 2016: British Medical Bulletin
Xing Xu, Xueyu Qi, Yufei Yan, Jin Qi, Niandong Qian, Lei Guo, Changwei Li, Fei Wang, Ping Huang, Hanbing Zhou, Min Jiang, Chunhao Yang, Lianfu Deng
Approaches of targeting excessive activation and differentiation of osteoclasts were considered as an effective treatment option for osteoporosis or osteopenia. In the present work, a series of rhein derivatives were synthesized and employed for their cytotoxicity screening against bone marrow-derived macrophages cells (BMMs) and their inhibition effects on osteoclasts activation and differentiation in vitro using an MTT assay and a TRAP activity assay respectively. Two rhein derivatives d6 and d11 inhibited BMMs activation and differentiation with 98% and 85% inhibitory activity respectively, without showing any cytotoxicity on BMMs...
November 10, 2016: European Journal of Medicinal Chemistry
Michael Regn, Bernhard Laggerbauer, Claudia Jentzsch, Deepak Ramanujam, Andrea Ahles, Sonja Sichler, Julia Calzada-Wack, Rory Koenen, Attila Braun, Bernhard Nieswandt, Stefan Engelhardt
A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol-(GPI) membrane anchor...
August 15, 2016: Journal of Molecular and Cellular Cardiology
Minsuk Kwon, Jin-Man Kim, Kyunghee Lee, So-Young Park, Hyun-Sook Lim, Taesoo Kim, Daewon Jeong
Osteoclast progenitors undergo cell cycle arrest before differentiation into osteoclasts, induced by exposure to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The role of such cell cycle arrest in osteoclast differentiation has remained unclear, however. We here examined the effect of synchronized cell cycle arrest on osteoclast formation. Osteoclast progenitors deprived of M-CSF in culture adopted a uniform morphology and exhibited cell cycle arrest at the G₀-G₁ phase in association with both down-regulation of cyclins A and D1 as well as up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1)...
2016: International Journal of Molecular Sciences
Adeleke H Aguda, Vincent Lavallee, Ping Cheng, Tina M Bott, Labros G Meimetis, Simon Law, Nham T Nguyen, David E Williams, Jadwiga Kaleta, Ivan Villanueva, Julian Davies, Raymond J Andersen, Gary D Brayer, Dieter Brömme
Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach...
August 26, 2016: Journal of Natural Products
Tsuyoshi Sato, Yuichiro Enoki, Yasushi Sakamoto, Kazuhiro Yokota, Masahiko Okubo, Masahito Matsumoto, Naoki Hayashi, Michihiko Usui, Shoichiro Kokabu, Toshihide Mimura, Yoshihiko Nakazato, Nobuo Araki, Toru Fukuda, Yasushi Okazaki, Tatsuo Suda, Shu Takeda, Tetsuya Yoda
OBJECTIVE: Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro...
September 2015: Heliyon
David Smith, Irina G Tikhonova, Heather L Jewhurst, Orla C Drysdale, Jan Dvořák, Mark W Robinson, Krystyna Cwiklinski, John P Dalton
Kunitz-type (KT) protease inhibitors are low molecular weight proteins classically defined as serine protease inhibitors. We identified a novel secreted KT inhibitor associated with the gut and parenchymal tissues of the infective juvenile stage of Fasciola hepatica, a helminth parasite of medical and veterinary importance. Unexpectedly, recombinant KT inhibitor (rFhKT1) exhibited no inhibitory activity toward serine proteases but was a potent inhibitor of the major secreted cathepsin L cysteine proteases of F...
September 9, 2016: Journal of Biological Chemistry
Jon J Vermeire, Brian M Suzuki, Conor R Caffrey
Hookworm infection is chief among soil-transmitted helminthiases (STHs) for the chronic morbidly inflicted. Deworming via mass drug administration (MDA) programs most often employs single doses of benzimidazole drugs to which resistance is a constant threat. To discover new drugs, we employ a hamster model of hookworm infection with Ancylostoma ceylanicum and use albendazole (ABZ; 10 mg/kg orally) as the gold standard therapy. We previously showed that a single oral 100 mg/kg dose of the cathepsin cysteine protease (CP) inhibitor, K11777, offers near cure of infection that is associated with a 95% reduction in the parasite's resident CP activity...
2016: Pharmaceuticals
Arun K Ghosh, Bhavanam Sekhara Reddy, Yu-Chen Yen, Emilio Cardenas, Kalapala Venketeswara Rao, Deborah Downs, Xiangping Huang, Jordan Tang, Andrew D Mesecar
Design, synthesis and evaluation of very potent and selective β-Secretase 2 (memapsin 1, BACE 2) inhibitors are described. The inhibitors were designed specifically to interact with the S2'-site of β-secretase 2 to provide >170,000-fold selectivity over β-secretase (BACE 1) and >15,000-fold selectivity over cathepsin D. BACE 2 is implicated in Type 2 diabetes. The studies serve as an important guide to selective BACE 2 inhibitors.
May 1, 2016: Chemical Science
Yonghui Dong, Hui Liu, Xuejun Zhang, Fei Xu, Liang Qin, Peng Cheng, Hui Huang, Fengjing Guo, Qing Yang, Anmin Chen
Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process...
2016: International Journal of Molecular Sciences
S Aubrey Stoch, Jeanine Ballard, Christopher Gibson, Filippos Kesisoglou, Rose Witter, Kelem Kassahun, Stefan Zajic, Anish Mehta, Christine Brandquist, Cynthia Dempsey, Daria Stypinski, Marc L Reitman
This open-label, 2-period study assessed the effect of multiple-dose administration of rifampin, a strong cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) inducer, on the pharmacokinetics of odanacatib, a cathepsin K inhibitor. In Period 1, 12 healthy male subjects (mean age 30 years) received a single dose of odanacatib 50 mg on Day 1 followed by a 28-day washout. In Period 2, subjects received rifampin 600 mg/day for 28 days; odanacatib 50 mg was co-administered on Day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and Day 1 of Period 1 and Day 14 of Period 2...
June 20, 2016: Journal of Clinical Pharmacology
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