Cathepsin S

CA C1 C01.034 Cathepsin S Tissue damage associated with inflammation... 

Macrophage invasion — the up-regulation of the macrophage mannose receptor, cathepsin S, and macrophage capping protein. Up-regulation of irramme response genes — overexpression of major histocompatibility complex (MHC) and IgG. 

OATENARY MODEL FOR COMPARTMENT ANALYSIS OATHEPSIN B OATHEPSIN D CATHEPSIN E OATHEPSIN G CATHEPSIN H CATHEPSIN L CATHEPSIN S CATHEPSIN T... 

Figure 10. Binding site anaiysis of different species can uncover potentiai probiems with ani-mai modeis for a given target. The Cathepsin S inhibitor JNJ 10329670 (exact molecule not shown) has an activity of 34 nM in humans, but shows sub-micromolar activity in dog, monkey, and cattie, and oniy micromoiar activity in mice. These activity differences can be expiained by the fact that in the dog, monkey and bovine Cathepisin S pockets, only two of the residues are non-conserved, whiie four of the residues are non-consen/ed in mice.

Cystcinyi protease Papain CalhepsiL B Cathepsin-Pf Calhepsin-L Calhepsin-M Calhepsin-N Cathepsin-S Calhepsin-T Proiine endopeptidase Interleukin-converting enzyme... 

Most of the lysosomal proteases called cathepsins are small 20- to 40-kDa glycoproteins found in all animal tissues.313 Most are cysteine proteases which function best and are most stable in the low pH reducing environment of lysosomes. They resemble papain in size, amino acid sequence, and active site structures. Papain is nonspecific but most cathepsins have definite substrate preferences. Cathepsin B is the most abundant. There are smaller amounts of related cathepsins H (an aminopeptidase)314 and L315 and still less of cathepsins C, K, and others. Cathepsin B is both an endopep-tidase and an exopeptidase.316 It acts on peptides with arginine at either Pj or P2 but also accepts bulky hydro-phobic residues in Pj and prefers tyrosine at P3.317 Cathepsin S is less stable at higher pH than other cathepsins and has a more limited tissue distribution, being especially active in the immune system.318 319... 

Catalytic dyad 620 Catalytic subunits 348 Catalytic triad 134, 611-614, 619, 635 of serine proteases 611—614 Cataracts 169 Catechol 838 Catecholamine(s) 553 Catechol O-methyltransferase (COMT) 591 Cathepsin(s) 619,621 G 610... 

Cystatin Cathepsin B Cathepsin L Cathepsin S Cathepsin H Papain... 

In addition to being an inhibitor of papain-like cysteine proteases, cystatin C has recently been shown be an efficient inhibitor of some of the cysteine proteases of another family of cysteine proteases, called the peptidase family C13, with human legumain as a typical enzyme (C6). Human legumain has, like cathepsin S, been proposed to be involved in the class n MHC presentation of antigens (M3). It has also been shown that the cystatin C inhibitory site for mammalian legumain does not overlap with the cystatin C inhibitory site for papain-like cysteine proteases (Fig. 1) and that the same cystatin C molecule therefore is able to simultaneously inhibit one cysteine protease of each type (A 10). 

Peptide vinyl sulfones NLVS, YLVS Cathepsin S and B... 

Cathepsin K inhibitors would prevent bone loss without inhibiting mineralization. The compound most tested, Balicatib, forms a covalent bond with the cysteine thiol group at the catalytic center of cathepsin K. Unfortunately, Balicatib tends to concentrate in all lysosomes, so that, over time, amounts in the body will increase and inhibit the catalytic thiol group of other cathepsins, notably cathepsin S which hydrolyzes proteins to peptides for antibody synthesis (antigen presentation). Nevertheless, no adverse side effects were reported in 140 postmenopausal women receiving once-a-day treatment with Balicatib for 12 months, but the possibility of increased infections after some years of taking Balicatib is a potential therapeutic problem. 

This is a fragment screening strategy in which substrates for a particular target protein are identified and then optimized rapidly. For example, substrates for the cysteinyl protease cathepsin S bearing a fluorogeific group were optimized for... 

Patterson, A. W., Wood, W. J. L., Hornsby, M., Lesley, S., Spraggon, G., Ellman, J. A. Identification of selective, nonpeptidic nitrile inhibitors of cathepsin S using the substrate activity screening method. J. Med. Chem. 2006,49, 6298-6307. 

Kong Y, Chung YB, Cho SY, Kang SY (1994) Cleavage of immunoglobulin G by excretory-secretory cathepsin S-fike protease of Spirometra mansoni plerocercoid. Parasitology 109 611-621... 

CATHEPSIN B HUMAN CATHEPSIN H HUMAN CATHEPSIN L HUMAN CATHEPSIN S HUMAN ACTINIDIN PAPAIN... 

Figure 11.2 Heterogeneous SAR combining continuous and discontinuous SAR. Four cathepsin S inhibitors dispiay different SAR behavior, inhibitors reiated by a continuous SAR have comparabie potency vaiues despite structurai variations (top). In the...

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