Protease inhibitor

Details Protease inhibitor Protease inhibitor

1991-10-24

1995-03-14

Wax, Robert A.

Chemistry: molecular biology and microbiology

Maintaining blood or sperm in a physiologically active state...

424 946, 435183, 435218, 514 12, 514902, 530350, A01N 100

Patent

active

053976940

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a novel protease-inhibitor,--which we called Gelin--, and to pharmaceutical and cosmetic preparations thereof, containing this compound.
Gelin is an inhibitor of human and porcine leucocyte-elastase and chymotrypsin. Gelin has specific antibiotic properties. It also relates to the novel use of Eglin, another chymotrypsin-inhibitor in cosmetic preparations.
Several diseases, like emphysema, arthritis, gingivitis, periodontitis and other inflammatory conditions occur due to tissue destruction caused by the enzyme Elastase. Elastases are the only serine proteases which are capable of solubilising fibrous proteins like elastin and collagen. They are chiefly present in pancreas and in the azurophilic granules of neutrophil leucocytes. Under normal physiological conditions, the proteolytic activity of the enzyme is kept under check by the excess of inhibitors present in plasma and other secretions. However, under diseased state, local deficiency of inhibitor leads to an imbalance resulting in tissue destruction, the underlying cause of various inflammatory conditions.
As an example this situation is described for gingivitis. Disorders of neutrophil-functions are often associated with abnormalities and conditions of the host, e.g.: diabetes mellitus, Down's syndrome, icthyosis, rheumatoid arthritis, cyclic neutropenia, agranulocytosis, Chediak-Higashi syndrome. (Cianciola, L. J., et al., Nature (1977), 265:445-447; Cohen, W. D., et al., J. Period (1961), 32:159-168). Polymorphonuclear (PMN)-derived neutral proteases and/or bacterial toxins directly or indirectly attach supporting tissues in the dento-gingival area so as to cause inflammation (Janoff, A., J. Am. Path. (1972), 68:538-623; Weiss, S. J., New Engl. J. Med. (1989), 320-6:365-376; Henson, P. M., et al., J. Clin. Invest. (1987), 79:669-674; Campbell, E. J., et al., J. Clin. Invest. (1982), 70:845-852; Lehrer, R. I., et al., Ann. Int. Med. (1989), 109:127-142). Gingival crevicular fluid from inflamed gingival tissues contains high levels of hydrolytic enzymes. (Cimasoni, G., Monographs in Oral Science, Vol. 12.ed., H. M. Myers, Philadelphia, Pa., Karger (1983)). Oxygen radicals have both bacteriostatic as well as tissue-destructing activities. (Schalkwijk, J., Thesis, Nijmegen Holland (1986)). This tissue-destructing activity is at discussion. (Weiss, S. J., New Engl. J. Med. (1989), 320-6:365-376; Henson, P. M., et al., J. Clin. Invest. (1987), 79:669-674; Dakin, H. D., Br. Med. J. (1915), 2:318-320). Chlorinated oxidating agents exert strong microbicidal activity (Clark, P. A., et al., Infect. Immun . (1986), 53-2:252-256) and are so as to be only suitable for use in a simple in-vitro buffer system (Dakin, H. D., Br. Med. J. (1916), 1:852-854; Dakin, H. D., JAMA (1917), 69:27-30). Already in 1917 the use of synthetic chloramines was recommended for irrigation of wounds. Still now, it remains dubious, whether the final oxidizing agent is HOCl or the derivative chloramine. (Weiss, S. J., et al., Science (1983), 222:625-628). While hydrolising, lysozomal enzymes, derived from PMN degranulation, are considered a threat to various tissue-constituents, (Weiss, S. J., New Engl. J. Med. (1989), 320-6:365-376; Campbell, E. J., et al., J. Clin. Invest. (1982), 70:845-852) natural serum protease-inhibitors (alpha 1 protease inhibitor and alpha macroglubolin) are at large inactivated by its myeloperoxidase-oxydizing system. (Weiss, S. J., New Engl. J. Med. (1989), 320-6:365-376; Kramps, J. A., et al., Clin. Science (1988), 75:53-62) Bacterial derived toxins (low-molecular weight metabolic products, glycoproteins, lipopolysaccharides, proteases ) are reported to initiate host tissue- and cell destruction as well as immune-cell activation. (Cimasoni, G., Monographs in Oral Science, Vol. 12.ed., H. M. Myers, Philadelphia, Pa., Karger (1983); Bom-vNoorloos et al., J. Clin. Periodontal. (1989), 16:412-418; Curtis, M. A., et al., J. Clin. Periodontal. (1989), 16:1-11; Carpenter, A. B., et al., Inf. Immun. (1984); 43-1:326-336). Some microorganis

REFERENCES:
Goldstein et al, Comp. Biochem. Physiol. B. Comp. Biochem. 84(1) pp. 117-124 1986.
Semeuller et al, Hope-Seyler's Z Physiol Chem 358(9) pp. 1105-1119 1977.

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