Cathepsins X and Β Display Distinct Activity Profiles That Can Be Exploited for Inhibitor Design

Ménard, Robert; Therrien, Christian; Lachance, P.; Sulea, Traian; Qi, Hongtao; Álvarez‐Hernández, Alejandro; Roush, William

doi:10.1515/bchm.2001.382.5.839

Cited by 12 publications

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“…256 Recently, a one amino acid CA-074 derivative, nPr-NH-(2S,3S)-Eps-Ile-OH, was designed to inhibit cathepsin X. 200,257 This is a specific, but not very potent, inhibitor for cathepsin X, with a 10-fold preference over cathepsins B and L (Table 24). Dipeptidyl epoxysuccinate derivatives have been successfully designed as selective inactivators of cathepsin B.…”

Section: Epoxysuccinyl Peptidesmentioning

confidence: 99%

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

et al. 2002

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Section: Epoxysuccinyl Peptidesmentioning

confidence: 99%

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

et al. 2002

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“…However, Ménard et al [92,93] showed that CA074 (3) was found to inactivate cathepsin B at least 34000-fold more efficiently than cathepsin X. Hence, it is demonstrated that specific inhibitors of cathepsin B or cathepsin X can be designed, taking advantage of the presence of the occluding loop in cathepsin B or the mini-loop in cathepsin X.…”

Section: Cysteine Proteases In Developmentmentioning

confidence: 99%

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Leung-Toung

Li²,

Tam³

et al. 2002

CMC

128

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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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Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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IntroductionThe ability of macrophages (Mfs) to progress to specific tissues, increase matrix remodeling, and induce angiogenesis is essential for their normal physiological function [1,2]. In addition, tissue infiltration of Mfs is also involved in pathological processes such as chronic inflammation, atherosclerosis, neurodegenerative disorders, and cancer progression [3]. The presence of Mfs Correspondence: Dr. Bojana Mirković e-mail: bojana.mirkovic@ffa.uni-lj.si within tumors is generally a marker of poor prognosis since they enhance angiogenesis and metastasis [4]. Furthermore, tumorassociated Mfs are emerging as essential matrix-remodeling cells during tumor-cell invasion. They have been reported to be present at high frequency at the invasive front of the tumor, where the breakdown of extracellular matrix (ECM) occurs [5]. Therefore, there is a great need to specifically control tissue infiltration of Mfs by targeting Mf migration-related molecules [6]. * These authors contributed equally to the present work. Eur. J. Immunol. 2012. 42: 3429-3441 Mf migration has been studied extensively in two dimensions (2D) on artificial substrates; however, in vivo Mfs migrate through physiological and pathological tissue and interact with the surrounding three-dimensional (3D) ECM, including basement membrane, collagen-rich interstitial matrices, and dense tissues such as tumors. Cells of different origins and/or at different differentiation stages use distinct mechanisms of cell motility in the 3D environment. In the mesenchymal mode, cells wider than the matrix pore size degrade the matrix via proteolytic and force-based matrix remodeling, thus migrating in a "path-generating" manner, while amoeboid cells squeeze through pre-existing pores in a proteaseindependent fashion in a "path-finding" mode [7,8]. The first 3D migration studies performed on cells of the immune system suggested that these cells migrate in a protease-independent fashion [7,9]. In contrast, a recent study demonstrated that Mfs adapt their migration strategy depending on the architecture of the 3D environment. In this study, Mfs were found to use the amoeboid migration mode in fibrillar collagen I and the mesenchymal migration mode in dense substrates, such as Matrigel and gelled collagen I [10].The invasion of cancer cells is facilitated by ECM-degrading invadopodia [11]. Podosomes are structures functionally similar to the invadopodia that are found in Mfs, osteoclasts, and DCs [12,13]. During migration on 2D surfaces [14], dot or ringlike podosomes form at the ventral surface of the migrating cells where they establish direct contact with the substratum and are also involved in matrix degradation [11]. Structurally, podosomes comprise a concentrated core of F-actin and actin-regulatory proteins [14]. Surrounding the core is a ring region that contains scaffolding-, signaling-, and integrin-binding proteins, including the typical focal adhesion proteins vinculin, talin, paxillin, and FAK [15]. When Mfs migrate in a 3D environment (i.e., migra...

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Cathepsins X and Β Display Distinct Activity Profiles That Can Be Exploited for Inhibitor Design

Cited by 12 publications

References 0 publications

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

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