Inhibitor of proteolytic enzymes

The failure in increasing residence time of mucoadhesive systems in the human intestinal tract has led scientists to the evaluation of multifunctional mucoadhesive polymers. Research in the area of mucoadhesive drug delivery systems has shed light on other properties of some of the mucoadhesive polymers. One important class of mucoadhesive polymers, poly(acrylic acid) derivatives, has been identified as potent inhibitors of proteolytic enzymes [72-74]. The interaction between various types of mucoadhesive polymers and epithelial cells has a direct influence on the permeability of mucosal epithelia by means of changing the gating properties of the tight jrmctions. More than being only adhesives, some mucoadhesive polymers can therefore be considered as a novel class of multifunctional macromolecules with a number of desirable properties for their use as delivery adjuvants [72,75]. 

Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Because of its rapid inactivation by plasma, chilling of the collecting tubes and addition of inhibitors of proteolytic enzymes are necessary when samples of blood are collected for immunoassay of circulating glucagon. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin. 

These products are biologically significant as some of these phosphonates have been observed to be potent inhibitors of proteolytic enzymes such as rennin and HIV protease. Stereoselective reduction of aminoketophosphonates using catecholborane provides a facile access to these biologically important molecules. 

Azaserine, 5-diazo-4-oxo-L-norvaline (DONV) and 6-diazo-5-ketonorleucine (DON) are other examples of mechanism-based irreversible inhibitors51). They are stable to nucleophilic attack, but on enzymatic protonation, they are converted to the reactive diazonium ions (30). N-Nitroso compounds have been proposed as irreversible inhibitors of proteolytic enzymes. N-Nitrosolactam (31) can inhibit chymotrypsin... 

Proteolytic enzymes (proteases) are involved in a wide variety of physiological processes including digestion, fertilization, coagulation, and the immune response. Outside of their normal environment, proteases can be extremely destructive and natural human plasma inhibitors inhibit most proteases that escape. Imbalance in protease-protease inhibitor systems can lead to a number of diseases of which pulmonary emphysema is one well-characterized example. This disease results when the protease elastase attacks elas-tin, the major elastic protein in the lung. Considerable effort has been devoted to the synthesis of inhibitors of proteolytic enzymes such as elastase for possible therapeutic use. In the future, specific and selective synthetic protease inhibitors should be useful for treating specific diseases that range from the common cold to chronic disorders such as emphysema. 

Smith, A. B., Ill, Keenan, T. R, Holcomb, R. C., Sprengeler, R. A., Guzman, M. C., Wood, J. L., Caroll, R J., Hirschmann, R. Design synthesis and crystal structure of a pyrrolinone-based peptidomimetic possessing the conformation of a (3-strand potential application to the design of novel inhibitors of proteolytic enzymes. J. Am. Chem. Soc. 1992,114, 10672-10674. 

Levy, M. R., and Chou, S. C. (1975). Inhibition of macromolecular synthesis in the malarial parasites by inhibitors of proteolytic enzymes. Experientia 31,52-54. 

Antinutrient factor removal Processed meats. Special diets. Specific protein inhibitors of proteolytic enzymes and amylases. Phytate. Gossypol. Nucleic acid. ... 

Pappas, P. W. and Uglem, G. L. (1990) Hymenolepis diminuta (Cestoda) liberates an inhibitor of proteolytic enzymes during in vitro incubation. Parasitology 101 455-464. 

A. B. Smith III, T. P. Keenan, R. C. Holcomb, P. A. Sprengeler, M. C. Guzman, J. L. Wood, P. J. Carroll, and R. Hirschmann,/. Am. Chem. Soc., 114,10672 (1992). Design, Synthesis, and Crystal Structure of a Pyrrolinone-Based Peptidomimetic Possessing the Conformation of a p-Strand Potential Application to the Design of Novel Inhibitors of Proteolytic Enzymes. 

The peptidic a-hydroxyl phosphonates present a promising and structurally unique class of transition-state analogue inhibitors of proteolytic enzymes and make the first disclosure of their application in preparing inhibitors of human renin. 

However, pulse-chase experiments in vitro, or the addition to extracts of inhibitors of proteolytic enzymes, have failed to provide any indication that cleavage or correct processing of large polypeptides occurred. However, one consistent finding is that uninfected cell extracts translate EMC virus ENA to produce a major polypeptide approximately 20,000 daltons larger than is produced by translation of the same ENA in extracts from infected cells (5, 12). The smaller product from infected cells is the same size as the... 

Leupeptide (the tripeptide inhibitor of proteolytic enzymes) can be delivered into the brain by means of liposomes obtained by reverse phase evaporation from a mixture of lecithine, cholesterol... 

Kassel 1, B. (1970). Inhibitors of proteolytic enzymes. Methods Enzymol. 19, 839-906. 

Inhibitors of proteolytic enzymes. Acc. Chem. Res. 7, 315-320. Melville, J. C., and Ryan, C. A. (1972). Chymotrypsin InTiibltor I from potatoes. Large scale preparation and characterization of Its subunit components. J. Biol. Chem. 247, 3445-3453. Menegatti, E., Tomatls, R., Guarner, M., and Scatturin, A. (1981). Conformational stability of porcine-pancreatic secretory trypsin Inhibitors (Kazal Inhibitors). Int. J. Pept. Protein Res. 17, 454-459. 

There are several reagents whose uses may be more restricted than those of inhibitors mentioned above but that nevertheless deserve discussion. Flavin-linked monoamine oxidase has been a fruitful enzyme for the development of new inhibitors. Besides being inhibited by acetylenic amines and olefinic amines, the enzyme is also inactivated by hydra-zides and cyclopropyl amines, e.g., the antidepressant drug tranylcypromine. Both of the latter reagents are first turned over by the enzyme before inhibition ensues, but the mechanisms of inhibition remain obscure. Recently, iV-nitroso compounds have been introduced as irreversible inhibitors of proteolytic enzymes. ... 

Inhibitors of proteolytic enzymes may play an important role in plant protection not only from harmful insects, but also other pests nematodes, the nematodes. Many nematodes are parasitic on plants and cause significant damage to agricultural production. In the gut of nematodes contains active cysteine and serine proteases, including chymotrypsin and kallikrein is similar. It is interesting that when infected with worms, among transcripts of tomato were found proteins related to the family of Kunitz inhibitor (SBH) (Valueva Mosolov, 2002 Schroeder et al., 1995). 

Valuev, I.L., Sytov, G.A., Valuev, L.I., Valueva, T.A., Ul yanova, M.V., Plate, N.A. (2001). Inhibitors of proteolytic enzymes in the therapy of diabetes. Russian Journal Voprosy Meditsinskoi Khimii, Vol. 47, No. 1, pp. 132-135, ISSN 0042-8809 Valueva, T.A., Mosolov, V.V. (2002). The role of inhibitors of proteolytic enzymes in plant protection. Uspekhi Biologicheskoi Khimmii, Vol. 42, pp. 193-216, ISSN 0006-2979 Vincent, D., Zivy, M. (2007). Plant proteome responses to abiotic stress. In Plant Proteomics, Eds. J. Samaj and J.J. Thelen, pp. 346-364, Springer, ISBN 13 978-3-540-72616-6, Germany... 

Fluoroalkyl P-amino alcohols are precursors of the corresponding fluoroalkyl peptidyl ketones which have been shown to be effective inhibitors of proteolytic enzymes, such as serine proteases/ (chymotrypsin/ elastases/ trypsin/ thrombin/ ) aspartyl proteasesor cysteine proteases, In some cases fluoroalkyl p-amino alcohols are themselves inhibitors of the same enzymes/ " This interest in these fluoroalkyl P-amino alcohols 1 aroused efforts for stereoselective and enantioselective synthetic methodsA number of approaches have been reported during these last years, either through the addition of trifluoromethyl equivalent anion to protected aldehyde or through the building block approach. However the main problem of all these approaches is the diastereoselectivity. 

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