Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Patent
1989-12-11
1991-08-06
Lee, Lester L.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
530331, 564152, 564159, C07K 506, C07K 508, C07K 510, C07K 700
Patent
active
050379577
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new compounds which are cysteine proteinase inhibitors interacting with the active sites of cysteine proteinases and, thus, inhibiting the degradation of peptides and proteins by cysteine proteinases.
Background
Cysteine proteinases are active in the intracellular protein and peptide catabolism of the body, in the extracellular degradation of collagen in the connective tissue of the body, and in the transformation of preproteins into their mature forms. If the activity of the cysteine proteinases is too high, different body tissues will be degraded at an excessive rate with consequent atrophy and impaired function. It is therefore of great importance that the activity of the cysteine proteinases of the body are accurately controlled. This is achieved, for example, in that the body fluids contain some ten proteins which inhibit cysteine proteinases. (Abrahamson M., Barrett A.J., Salvesen G., and Grubb A.: Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. (1986) J. Biol. Chem. 261, 11282-11289).
Ischemic injuries, e.g. in connection with cardiac infarction, mean that body tissues are damaged by lack of oxygen. The extent of the final tissue damage increases since the cells primarily damaged by lack of oxygen release intracellular cysteine proteinases, which attack the surrounding normal tissue. The content of protein cysteine-proteinase inhibitors in the body fluids contributes to minimizing such secondary tissue damage which appears in connection with every ischemic injury.
Cysteine proteinases which are injected in different body fluids cause no damage as long as the inhibiting capacity of the protein cysteine-proteinase inhibitors of the body fluids is not exceeded. Proteinase overloading of the inhibitors entails very serious functional disorders, primarily hemorrhages. (Garvin P., Jennings R., Smith L., and Gesler R.: Chymopapain: A pharmacologic and toxicologic evaluation in experimental animals. (1965) Clin. Orthop. 41, 204-223). It may be mentioned that disc degeneration has been successfully treated with injections of cysteine proteinases in the damaged discs. When, unintentionally, the whole or part of the injection comes into the cerebrospinal fluid, severe cerebral hemorrhage is caused in the patients as a consequence of proteinase overloading of the total inhibiting capacity of the low content of protein cysteine-proteinase inhibitors in the cerebrospinal fluid. (Davies R., North R., Campbell J., and Suss R.: Multiple cerebral hemorrhages following chymopapain chemonucleolysis. (1984) J. Neurosurg. 61, 169-171). It has also been demonstrated that in connection with certain spontaneous cerebral hemorrhages, the patients exhibit a considerably reduced content of the protein cysteine-proteinase inhibitors in the cerebrospinal fluid. (Grubb A., Jensson O., Gudmundsson G., Arnason A., Lofberg H., and Malm J.: Abnormal metabolism of .gamma.-trace alkaline microprotein. The basic defect in hereditary cerebral hemorrhage with amyloidosis. (1984) N. Engl. J. Med. 311, 1547-1549).
When the normal body tissue is penetrated by certain malignant cells and microorganisms, these malignant cells and microorganisms use cysteine proteinases to break down the resistance of the normal body tissue to such penetration. The protein inhibitors of cysteine proteinases in the body therefore are considered to play an important role for resisting such undesired tissue penetration. (Giraldi T., Sava G., Kopitar M., Brzin J., and Turk V.: Antimetastatic effects and tumour proteinase inhibition by spleen intracellular inhibitors of neutral proteinases. (1981) Eur. J. Cancer Clin. Oncol. 17, 1301-1306).
Many microorganisms, such as bacteria and viruses, produce their proteins as very large protein molecules which are then processed by proteolysis into the mature active smaller proteins used for the growth of the microorganisms and the invasion of the patient. If the initial protein st
REFERENCES:
patent: 4100117 (1978-07-01), Shields
The Journal of Biological Chemistry, vol. 262, No. 20, Issued Jul. 15, 1987, pp. 9688-9694, "Identification of the Probable Inhibitory Reactive Sites of the Cysteine Proteinase Inhibitors Human Cystatin C and Chicken Cystatin".
Green et al., J. Biol. Chem. 1981, 256(4):1923-1928.
Abrahamson Magnus
Grubb Anders
Trojnar Jerzy
Lee Lester L.
Maebius Stephen B.
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