Cathepsin D and

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

While the exact mechanism of ceramide-mediated regulation of most of the above proteins is still unknown, ASM-released ceramide binds directly to PLAa and cathepsin D (Huwiler et al, 2001 Heinrich et al., 1999). Binding of ceramide to cathepsin D in endosomes triggers autocatalytic cleavage of cathepsin to its active form (Heinrich et al, 1999). However, the physiological role of ceramide binding to cathepsin D and PLA2 for apoptosis stiU remains to be determined. 

Potent inhibitor of add proteases, including pepsin, renin and cathepsin D and many microbial aspartic proteases... 

The down-regulated proteins in HCC tissues have been identified. Park et al. identified aldehyde dehydrogenase 2 (25) and ferritin light chain (32). Kim et al. identified HSP 27, cathepsin D, and others (26). Lim et al. identified cytochrome B5, liver car-boxyesterase, and others (27). Li et al. identified SOD 1, aldolase B, and others (28). Fujii et al. identified galectin-1 (29). Kim et al. identified argininosuccinate synthase, carbamoyl-phosphate s mthase, and others (31). Table 1 shows the summary of the proteins whose expression was different between HCC cancer tissues and non-cancerous tissues. 

Aspartic proteases have also been proposed as the ECE of primary interest. Enzymes of this type have been isolated from a range of tissues and have been shown to cleave big ET-1 to ET-1. The case has been proposed for pepsin, cathepsin D and cathepsin E being the important enzyme, the latter being very attractive since the human enzyme has been shown to give only ET-1 and the C-terminal fragment (22-38) as big ET-1 breakdown products [62]. However, their physiological roles continue to be questioned as they require an acidic environment for activity. Inhibitors of the aspartic protease from rat lung tissue have been reported [63] but there is no information on inhibitors of the other aspartic enzymes. 

Upregulation of the lysosomal system has been suggested to contribute to the pathogenesis of AD. Okadaic acid (OA), a protein phosphatase-2A inhibitor, increases tau phosphorylation, p-amyloid deposition, and neuronal cell death. While inhibition of cathepsin D and L failed to protect neurons from OA-induced cell death, CA074-Me, a cathepsin B inhibitor, conferred a protective effect. CA-074Me reduced APP accumulation and a-spectrin cleavage, similar to the effect of calpain inhibition [507]. 

Alzheimer s disease is characterized by plaques in the brain consisting primarily of the 40-42 amino acid amyloid / -peptide (A/ ) [258]. AfS derives from proteolysis of the amyloid precursor protein (APP) by the fS and y sec-retases to create the N and C-termini of the peptide respectively [259]. The / -secretase has recently been identified as a 501 amino-acid transmembrane protein by several research groups [260-263], The enzyme, variously named BACE, memapsin2, and Asp2, is an aspartic protease related to pepsin, cathepsin D, and renin, with all the properties expected of the /i-sccrctasc. 

Arnold D, Keilholz W, Schild H-J, Dumrese T, Stevanovic S, Rammensee H-G (1997) Substrate specificity of cathepsins D and E determined by N-lerminal and C-terminal sequencing of peptide-pools, Eur J Biochem 249 171-179. 

Theodorescu D, Broder SR, Boyd JC, et al. Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate. Cancer. 1997 80 2109. 

Ogino S, Cohen ML, Abdul-Karim FW. Atypical teratoid/ rhabdoid tumor of the CNS cytopathology and immunohistochemistry of insulin-like growth factor-II, insulin-like growth factor receptor type 1, cathepsin D, and Ki-67. Mod Pathol. 1999 12 379-385. 

Cerebrospinal Fluid. The proteome of cerebrospinal fluid can provide clues to several neurological disorders, including Alzheimer disease, Parkinson disease, and multiple sclerosis. This study has identified five proteins involved in amyloid-beta metabolism and other metabolisms. These include apolipoprotein Al, cathepsin D, and hemopexin, which were downregulated in Alzheimer patients the transthyretin and pigment epidermal factors were elevated. 

Sherman, I. W., and Tanigoshi, L. (1983a). Purification of Plasmodium lophurae cathepsin D and its effects on membrane proteins. Mol. Biochem. Parasitol. 8, 207-226. 

Even though the microfluidic-MS analysis was performed with low injection volumes, it enabled the identification of five putative biomarkers 39,40 proliferating cell nuclear antigen (PCNA), cathepsin D and keratins K8, K18 and K19 (Table 7.1). All corresponding peptides that identified these proteins had p < 0.001, confirming the reliability of the match. PCNA is a protein involved... 

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