Human cathepsin

Fig. 13.4. Comparison of the predicted three-dimensional structure of an H. contortus gut-derived cysteine protease (HMCP1) with that of human cathepsin B.

Bromme, D. and Okamoto, K. (1995). Human cathepsin 02, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol. Chem. 376,379-384. 

The amino acid sequences of aspergillopepsin I, penicillopepsin, rhizopuspepsin, endothiapepsin, candidapepsin, mucorpepsin, porcine pepsin, and human cathepsin D are aligned. These enzymes are classified into two groups (class I and II). Class I enzymes have... 

Diazetidin-2,4-dione has been found to be a chymase inhibitor (IC50 4.0nM). It has been found that 1,3-diazetidin-2,4-dione derivatives possess high activities against bovine pancreatic cr-chrymotrypsin, human cathepsin G, and human neutrophil elastase. Some of the derivatives of l,3-diazetidin-2,4-diones have been shown to be effective as a scaffold for serine protease inhibitors <2001BML1691>. Further, 1,3-diazetidinone containing scaffolds have been found to possess potential antibacterial properties (Section 2.13.7.3). 

Rehault, S. et al. 1999. New sensitive fluorogenic substrates for human cathepsin G based on the squence of serpin-reactive site loops. J. Biol. Chem. 274, 13810-13817. 

Half-lives (t /2, s) of Free (a) Human Cathepsin B and (b) Papain on Interactions with Cystatins in Human Body Fluids... 

Fig. 5.3 Crystal structure of acyclic diaminoketone (Fig. 5.4a) bound in the active site of human cathepsin K (PDB ID code 1AU2) [15].

Tab. S.1 (f, app values versus human cathepsin K for acyclic and constrained analogues [19].

Fig. 5.7 Crystal structure of azepanone (Fig. 5.4e) bound in the active site of human cathepsin K (PDB ID code INLJ) [19]. The two aromatic ring systems of the bound azepanone have been altered slightly from the costal structure, to make these groups completely planar. One possible equatorial con-former of the S diastereomer was generated, and the azepanone of this model (purple) was superimposed onto that of the bound inhibitor (color-by-atom). The azepanone and the pyridyl sulfonamide of the model (not shown for clarity) overlay reasonably well with the bound inhibitor, but the unprime side does not. Selected atoms of cathepsin K residues that clash with the model are shown in cyan.

Peptide Fluoromethyl Ketones Fluoroalkyl derivatives of the peptide chloromethyl ketones have been prepared in an attempt to improve specificity by reducing nonspecific alkylation at cysteine residues (Rasnick, D., Synthesis of peptide fluoromethyl ketones and the inhibition of human cathepsin B, Anal. Biochem. 149, 461 65, 1985). Nonspecific reaction with sulfydryl groups such as those in glutathione was reduced there was still reaction with active site cysteine although at a slower rate than with the chloroalkyl derivative (16,200 M s vs. 45,300 1 2 21.9 min. vs. 

K., Neurath, H. and Woodbury, RG. (1985). Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dc skin proteases and human cathepsin G with peptide-4-nitroanilide substrates and with peptide chloromethyl ketone and sulphonyl fluoride inhibitors. Biochemistry 24, 2048-2058. 

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

G. Salvesen, D. Farley, J. Shuman, A. Ptzybyla, C. Reilly, and J. Travis. Molecular cloning of human cathepsin G structural similarity to mast cell and cytotoxic T lymphocyte proteinases. Biochemistry 26 2289 (1987). 

Recently, Fmoc-N-protected (3-amino acid synthons have been prepared and used for the synthesis of (3-peptides on solid phase [103]. This methodology facilitates enormously the search for new bioactive compounds, above all through the generation of combinatorial (3-peptide libraries. In this context, (3-amino acids have been used as building blocks for RGD cyclic peptides and for the synthesis of an inhibitor of human cathepsin L, previously identified by screening and deconvolution of pentapeptide amide collections [104,105]. 

Although once in a while surprisingly simple molecules will show activity. For example A-cyanopyrrolidine is a micromolar, somewhat selective inhibitor of some cysteine proteases. See Falgueyret, J.-P. et al. Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J. Med. Chem. 

Nomnra, T., Eujishima, A., Fujisawa, Y., 1996. Characterization and crystallization of recombinant human cathepsin L. Biochem. Biophys. Res. Commun. 228, 792-796. 

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