Cathepsins play an important role in the degradation of host connective tissues, the generation of bioactive proteins and antigen processing. They have been implicated in osteoporosis, muscular dystrophy, rheumatoid arthritis, bronchitis, emphysema, viral infection, cancer metastasis and neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease. Recently, increased interest in cathepsin inhibitors has been generated with potential therapeutic targets, such as cathepsin K or cathepsin L for osteoporosis and cathepsin S for immune modulation. Of the 53 patents assessed in this review, granted between March 1998 and February 2001, there were 40 patents related to cysteine proteinase inhibitors, 7 related to aspartic proteinase inhibitors and 6 related to serine proteinase inhibitors. Of the 40 patents, 14 disclosed the novel compounds that were more selective against cathepsin K or cathepsin S than cathepsin B and cathepsin L. The compounds, showing experimental evidences, were evaluated and their biological activities in animal models determined. However, only 4 patents presented significant results in vivo. These patents may be a basis for promoting further evaluation and developing second generation cathepsin inhibitors.Keywords: aspartic, cathepsin inhibitor, cysteine proteinase inhibitor, proteinase inhibitor, selectivity, serine proteinase inhibitor Expert Opin. Ther. Patents (2002) 12(3):419-432 Recent developments of cathepsin inhibitors and their selectivity 420 Expert Opin. Ther. Patents (2002) 12(3)cysteine proteinase inhibitors, aspartic proteinase inhibitors, or serine proteinase inhibitors. The selectivity and clinical applications of these three classes of inhibitors is also described. Discussion Cysteine proteinase inhibitorsThe most important endogenous inhibitors of cysteine proteinases cathepsins B, H, L and S are cystatins [16][17][18]. Cystatins are divided into three subfamilies. Members of family I, or stefins, are small proteins of ~ 100 amino acids, which have no internal disulfide bonds [19]. The inhibitors of family II contain two disulfides and have ~ 120 amino acids. The members of family III are the larger glycoproteins, called kininogens [19]. Human cystatin A consists of 98 amino acid residues and belongs to family I. The inhibitory activity of cystatin toward papain-like proteinase is due to the interaction of the wedge-shaped edge of the inhibitor with the active-site cleft of the enzyme [19,20]. The inhibitory wedge is formed by three segments of the protein, the N-terminal end of the chain and two hairpin loops, one central and one closer to the C-terminus. The N-terminal region of the cystatin C, especially the residues Leu 9 , Val 10 and Gly 11 , is essential for inhibition [18,21]. Aberrant regulation of cystatin C associated with increased production and secretion of cysteine proteinase was observed in the invasive phenotype of many metastatic cell types [22][23][24][25].E64,1-[L-N-(trans-epoxysuccinyl)-leucyl] amino-4-guanidinobutane, was isolated from ...
Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competative manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin.
Human 92-kDa type IV collagenase (gelatinase B), a family of matrix metalloproteinases (MMP), play important roles in the degradation of the basement membrane and the migration of leukocytes and metastatic tumor cells during inflammation and invasion. To investigate the biochemical and enzymatic characteristics of human neutrophil type IV collagenase, the enzyme was extracted from human leukocytes and purified by a combination of Ultrogel AcA 54 and Bio-Rex 70 chromatographies. The purified enzyme showed a single band of molecular weight of 92 kDa on SDS-PAGE. Human neutrophil type IV collagenase degraded gelatin by cleaving the specific sites, but did not affect intact type I collagen. Human 92-kDa type IV collagenase activity was inhibited by EGTA, EDTA and tetracycline. Tetracycline showed the strongest inhibitory effect on the gelatinolytic activity of the 92-kDa type IV collagenase. These inhibitory effects may be due to the chelation effect of these agents since 92-kDa type IV collagenase is a metalloenzyme.
Human neutrophil elastase (HNE, IEC 3. 4. 21. 37) is a causative factor of inflammatory diseases, including emphysema and rheumatoid arthritis. Enzymatic characterization is important for the development of new drugs involved in the regulation of this enzyme. In this study, we investigated the enzymatic and biochemical properties of five different elastolytic enzymes, with a molecular mass between 24 kDa and 72 kDa. Three elastases, molecular masses of 27, 29, 31 kDa, might be elastase isozymes that have the same NH2-terminal amino acid sequences of Ile-Val-Gly-Gly-Arg-Arg-Ala. The 24-kDa enzyme, which showed the identical NH2-terminal amino acid sequences to elastase, was a degraded fragment of native elastase. The elastolytic activity was conserved at the 6/7 domain of the NH2-terminal region. The inhibitory characteristics of PMSF, DipF were the same as those of native elastases. The 72-kDa molecule, which showed elastolytic activity, might be a trimer formed between native elastases (31 kDa and 29 kDa) and a cathepsin G-like enzyme, which did not show elastolytic activity but enhanced the elastolytic activity of neutrophil elastase. Although this cathepsin G-like enzyme showed weak cathepsin G activity, it has distinguishable NH2-terminal sequences of Ile-Val-Gly-Gly-Ser-Arg-Ala- from those of elastase or cathepsin G. The potentiation of elastolytic activity could be a result of the trimerization of native elastase with a cathepsin G-like enzyme, and was then weakly inhibited by serine protease inhibitors, such as PMSF, DipF. Therefore, we suggest the cathepsin G-like enzyme to be a novel enzyme, which has an important role in the development of inflammation.
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