Cathepsin D

Cathepsin D (from bovine spleen) [9025-26-7] Mr 56,000, [EC 3.4.23.5]. Purified on a CM column after ammonium sulfate fractionation and dialysis, then starch-gel electrophoresis and by ullracentrifugal analysis. Finally chromatographed on a DEAE column [Press et al. Biochem J 74 501 I960],... 

Cathepsin D Spleen, liver, and many other animal tissues Lysosomal digestion of proteins... 

Cathepsins are intracellular proteinases that reside within lysosomes or specific intracellular granules. Cathepsins are used to degrade proteins or pqffides that are internalised from the extracellular space. Some cathepsins such as cathepsin-G or cathepsin-K may be released from the cell to degrade specific extracellular matrix proteins. All cathepsins except cathepsin-G (serine) and cathepsin-D (aspartyl) are cysteine proteinases. 

AA A1 A01.009 Cathepsin D Diagnosis and prognosis of breast and other cancers... 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Cathepsin D. The design of inhibitors of the aspartyl protease cathepsin D started from a virtual library of peptide analogs that contained the typical hydroxyethylamine isoster for the cleavable peptide bond. As the availability of starting materials would have generated a library of about 1 billion compounds, virtual screening was applied to reduce this multitude of candidate structures to a reasonable number. The backbone of a peptide... 

Plasmepsin II. The malarial aspartyl protease plasmepsin II has a significant homology (35%) to cathepsin D. Correspondingly, the very same approach as for the cathepsin D inhibitors (see above) was followed. The best inhibitors have Ki values of 2-10nM, a molecular weight <650, moderate selectivity vs. cathepsin D, the most closely related human protease, log P values <4.6, and no apparent binding to human serum albumin, for example, compound 36 Ki plasmepsin II = 2.0nM, Ki cathepsin D = 9.8nM Fig. 16.5) [111]. 

CCL3 Cathepsin D Degradation from Cterm Wolf et al. (2003)... 

Wolf M, Clark-Lewis I, Buii C et al (2003) Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Am J Pathol 162 1183-1190... 

The carboxyl proteases are so called because they have two catalytically essential aspartate residues. They were formerly called acid proteases because most of them are active at low pH. The best-known member of the family is pepsin, which has the distinction of being the first enzyme to be named (in 1825, by T. Schwann). Other members are chymosin (rennin) cathepsin D Rhizopus-pepsin (from Rhizopus chinensis) penicillinopepsin (from Penicillium janthinel-lum) the enzyme from Endothia parasitica and renin, which is involved in the regulation of blood pressure. These constitute a homologous family, and all have an Mr of about 35 000. The aspartyl proteases have been thrown into prominence by the discovery of a retroviral subfamily, including one from HIV that is the target of therapy for AIDS. These are homodimers of subunits of about 100 residues.156,157 All the aspartyl proteases contain the two essential aspartyl residues. Their reaction mechanism is the most obscure of all the proteases, and there are no simple chemical models for guidance. 

Poly(L-lysine) has also been suggested as a carrier for pepstatin, a specific inhibitor of the lysosomal proteinase cathepsin D, responsible for causing muscle-wasting diseases, such as muscular dystrophy [257],... 

Figure 1. Chemical structures of representative ligands investigated A) biotin, B) 2-(4 -hydroxyazobenzene) benzoic acid (HABA), C) charged (X=CH2) and neutral (X=NH2+) carboxylate MMP inhibitors, D) TIBO scaffold, E) sustiva, and F) hydroxyethylamine scaffold. The biotin derivatives," MMP inhibitors,19 TIBO analogs,21 and cathepsin D inhibitors22 derived from structures A), C), D), and F), respectively, have been published elsewhere.

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. 

C. E. Lee, E. K. Kick, J. A. Ellman, General Solid-Phase Synthesis Approach to Prepare Mechanism-Based Aspartyl Protease Inhibitor Libraries. Identification of Potent Cathepsin D Inhibitors. J. Am. Chem. Soc 1998, 120, 9735-9747. 

Other collaborative work from our laboratories has recently shown a second biologically active peptide to be generated by cathepsin D (as well as pepsin)... 

Degradation of these natural barriers by invading cancer cells is believed to be brought about by the release of a number of different proteases from the invading tumor. The proteases implicated in degradation of the extracellular matrix include the urokinase form of plasminogen activator (uPA), cathepsin B (CB), cathepsin D (CD), and various metalloproteases. These proteases appear to act in a cascade manner (Fig. 2) (S2). A brief description of the main proteases involved in metastasis now follows. 

Bl 1. Briozzo, P., Morisset, M., Capony, F., Rougeot, C., and Rochefort, H., In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. Cancer Res. 48, 3688-3692 (1988). 

II. Isola, J., Weitz, S., Visakorpi, T., Holli, K., Shea, R., Khalbaz, N., and Kallioniemi, O.-P., Cathepsin D expression detected by immunohistochemistry has independent prognostic value in auxiliary node-negative breast cancer. J. Clin. Oncol. 11, 36-43 (1993). 

R3. Rochefort, H., Cathepsin D in breast cancer A tissue marker associated with metastasis. Eur. 

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