An epoxysuccinic acid derivative(loxistatin)-induced hepatic injury in rats and hamsters

Fukushima, Kiyomi; Arai, Masayuki; Kohno, Yoshiro; Suwa, Toshio; Satoh, Tetsuo

doi:10.1016/0041-008x(90)90353-v

Cited by 19 publications

(13 citation statements)

References 24 publications

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“…However, an early pilot study testing the efficacy of Bestatin and Loxistatin, both of which are general inhibitors for multiple cathepsin family members, showed improved muscle function in infant DMD patients, but the effects were not reproduced in juvenile patients (34). This negative result might be explained by the lack of specificity and harmful off-target effects of these agents (35,36).…”

Section: Discussionmentioning

confidence: 91%

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

Tjondrokoesoemo

Schips

Sargent

et al. 2016

Journal of Biological Chemistry

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Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin protein compromises the stability of the sarcolemma membrane surrounding each muscle cell fiber, leading to membrane ruptures and leakiness that induces myofiber necrosis, a subsequent inflammatory response, and progressive tissue fibrosis with loss of functional capacity. Cathepsin S (Ctss) is a cysteine protease that is actively secreted in areas of tissue injury and ongoing inflammation, where it participates in extracellular matrix remodeling and healing. Here we show significant induction of Ctss expression and proteolytic activity following acute muscle injury or in muscle from mdx mice, a model of DMD. To examine the functional ramifications associated with greater Ctss expression, the Ctss gene was deleted in the mdx genetic background, resulting in protection from muscular dystrophy pathogenesis that included reduced myofiber turnover and histopathology, reduced fibrosis, and improved running capacity. Mechanistically, deletion of the Ctss gene in the mdx background significantly increased myofiber sarcolemmal membrane stability with greater expression and membrane localization of utrophin, integrins, and ␤-dystroglycan, which anchor the membrane to the basal lamina and underlying cytoskeletal proteins. Consistent with these results, skeletal musclespecific transgenic mice overexpressing Ctss showed increased myofiber necrosis, muscle histopathology, and a functional deficit reminiscent of muscular dystrophy. Hence, Ctss induction during muscular dystrophy is a pathologic event that partially underlies disease pathogenesis, and its inhibition might serve as a new therapeutic strategy in DMD.

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Section: Discussionmentioning

confidence: 91%

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

Tjondrokoesoemo

Schips

Sargent

et al. 2016

Journal of Biological Chemistry

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“…E-64d (loxistatin), a pro-drug of E64c, was tested in humans in Japan for the treatment of muscular dystrophy [169], but development was stopped in 1992 in phase III clinical trial [170]. While loxistatin (E-64d) caused hepatic injury in rats [171], E-64 showed teratogenic effects on rat embryogenesis [172].…”

Section: Cathepsin B Inhibitorsmentioning

confidence: 99%

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung

Zhao²,

Li³

et al. 2006

CMC

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A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.

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“…A derivative of E-64, loxistatin (E-64d, 10) which is a prodrug of E-64c (11), was tested in Japan for the treatment of muscular dystrophy, but development was stopped in 1992 in phase III clinical trial [108]. Loxistatin (10) was found to cause hepatic injury in rats [109].…”

Section: Inhibitors Of Cathepsin Bmentioning

confidence: 99%

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Leung-Toung

Li²,

Tam³

et al. 2002

CMC

129

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Biological thiol-dependent enzymes have recently received extensive attention in the literature because of their involvement in a variety of physiopathological conditions. The active thiol groups of these enzymes are derived from the cysteine residues present. Hence, in a biological system, the selective reversible or irreversible inhibition of the activity of these enzymes by modification of the thiol moiety may potentially lead to the development of a chemotherapeutic treatment. Despite all the research efforts involved in the attempt to develop potential chemotherapeutic treatments for the major diseases involving cysteine proteases, there are in fact no such treatments available yet. However, AG7088 (1) an inhibitor of rhinovirus-3C is in phase II/III clinical trial for the treatment of common cold and VX-740 (2, pralnacasan) an inhibitor of caspase-1 is in phase II clinical trial as an anti-inflammatory agent for rheumatoid arthritis. Several other cysteine protease inhibitors (i.e., cathepsin K, and S) are in pre-clinical evaluation or pre-clinical development. Structure-based drug design approaches have been instrumental in the development of these inhibitors. Intensive biochemical studies on the cysteine proteases have shed some light on some potential targets for therapeutic development. In addition, new techniques and new ideas are constantly emerging. As such, an up-to-date review of the literature on thiol-dependent enzymes as potential targets and their inhibitors designed from peptidic, modified peptidomimetic scaffolds and from small heterocyclic molecules is presented.

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An epoxysuccinic acid derivative(loxistatin)-induced hepatic injury in rats and hamsters

Cited by 19 publications

References 24 publications

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Thiol-Dependent Enzymes and Their Inhibitors: A Review

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