Structure-based development of specific inhibitors for individual cathepsins and their medical applications

Katunuma, Nobuhiko

doi:10.2183/pjab.87.29

Cited by 50 publications

(53 citation statements)

References 26 publications

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“…9). Similar results were obtained with E-64, another cysteine protease inhibitor (32). These findings suggest that cathepsin B and other cathepsins contribute to the detachment of dead cells.…”

Section: Discussionsupporting

confidence: 84%

“…It was difficult to investigate all the contributions of the many lysosome-hydrolyzing enzymes regarding streptococcal H 2 O 2 -mediated cell death; however, we investigated the possible contribution of cathepsin B using CA-074 Me, a specific cathepsin B inhibitor (32). Contrary to our expectations, the inhibitor did not inhibit cell death (Fig.…”

Section: Discussionmentioning

confidence: 62%

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Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

et al. 2016

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c Streptococcus oralis, an oral commensal, belongs to the mitis group of streptococci and occasionally causes opportunistic infections, such as bacterial endocarditis and bacteremia. Recently, we found that the hydrogen peroxide (H 2 O 2 ) produced by S. oralis is sufficient to kill human monocytes and epithelial cells, implying that streptococcal H 2 O 2 is a cytotoxin. In the present study, we investigated whether streptococcal H 2 O 2 impacts lysosomes, organelles of the intracellular digestive system, in relation to cell death. S. oralis infection induced the death of RAW 264 macrophages in an H 2 O 2 -dependent manner, which was exemplified by the fact that exogenous H 2 O 2 also induced cell death. Infection with either a mutant lacking spxB, which encodes pyruvate oxidase responsible for H 2 O 2 production, or Streptococcus mutans, which does not produce H 2 O 2 , showed less cytotoxicity. Visualization of lysosomes with LysoTracker revealed lysosome deacidification after infection with S. oralis or exposure to H 2 O 2 , which was corroborated by acridine orange staining. Similarly, fluorescent labeling of lysosome-associated membrane protein-1 gradually disappeared during infection with S. oralis or exposure to H 2 O 2 . The deacidification and the following induction of cell death were inhibited by chelating iron in lysosomes. Moreover, fluorescent staining of cathepsin B indicated lysosomal destruction. However, treatment of infected cells with a specific inhibitor of cathepsin B had negligible effects on cell death; instead, it suppressed the detachment of dead cells from the culture plates. These results suggest that streptococcal H 2 O 2 induces cell death with lysosomal destruction and then the released lysosomal cathepsins contribute to the detachment of the dead cells. Streptococcus oralis, a commensal bacterium in the oral cavity, belongs to the group of oral inhabitants of the mitis group of streptococci (1-4). Members of this group, including Streptococcus sanguinis and Streptococcus gordonii, are dominant colonizers of human teeth and are involved in dental plaque formation (1-3). Pathogenic streptococcal species, such as Streptococcus pneumoniae and Streptococcus mitis, are also members of the mitis group (2, 4-6). This group has been implicated as a possible cause of human cardiovascular diseases, including infective endocarditis and atherosclerosis. S. oralis is frequently isolated from cases of infective endocarditis (7-10), and ribosomal DNAs of the mitis group were detected in atheromatous plaque (11). The rate of bacteremia caused by members of the mitis group of streptococci is comparable to that caused by group A or B streptococci (12).The members of the mitis group of streptococci produce hydrogen peroxide (H 2 O 2 ) (2, 13, 14), which is important in bacterial competition in microbial communities, such as oral biofilms (13,14). S. sanguinis and S. gordonii produce H 2 O 2 in quantities sufficient to reduce the growth of many oral bacteria, including the cariogenic bacterium Strepto...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 62%

Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

et al. 2016

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“…In the field of proteases, the move from bench to bedside encompasses a wide range of protease inhibitors that can be applied to treat various diseases, mostly with the aim to limit excessive proteolytic activities. Examples are hypertension (ACE inhibitors), diabetes (DPPIV inhibitors), AIDS (HIV protease inhibitors), and many more, while anti-cancer therapies have proved more difficult to achieve (Bromme and Lecaille 2009;Chen et al 2011;Coussens et al 2002;Demuth et al 2005;Huber and Groll 2012;Katunuma 2011;Li et al 2014;Stein and Groll 2014;Turk 2006). While clinical trials with inhibitors of MMPs were ill-defined and entered the clinical phase prematurely, the example of bortezomib as a proteasome inhibitor that blocks cellular protein turnover, and therefore acts in a much less specific manner, has been used successfully to treat certain tumors.…”

Section: The Protease Family Businessmentioning

confidence: 99%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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“…By using this inhibitor as a frame and applying X-ray crystal structures of cathepsins B and L, specific inhibitors of these enzymes were designed (Fig. 3), prepared and shown to have promising anticancer activity in animal studies (Katunuma, 2011). Traditionally, secondary metabolites from streptomyces show a wide range of diversity with respect to their biological activity and chemical nature.…”

Section: Inhibitors From Natural Sourcesmentioning

confidence: 99%

Inhibitors of Proteinases as Potential Anti-Cancer Agents

Gluza¹,

Kafarski²

2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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Structure-based development of specific inhibitors for individual cathepsins and their medical applications

Cited by 50 publications

References 26 publications

Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Inhibitors of Proteinases as Potential Anti-Cancer Agents

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