Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-12-02
2000-09-12
Johnson, Nancy A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
4241301, 4241371, 436827, 530300, 5303871, 5303875, 530396, A61K 3800, A61K 39395, C07K 400, C07K 1618
Patent
active
061178365
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to agents that inhibit the activation of Factor X, and thus are candidates for treatment or prevention of thrombosis. More specifically, the invention concerns agents that affect the normal glycosylation pattern of Factor X and thus diminish its conversion to its activated form. The activated form of Factor X, Factor Xa, is essential for the formation of thrombin, which is, in turn, essential for the formation of blood clots, as well as an inducer of smooth muscle cell proliferation.
BACKGROUND ART
Thrombin is a multifunctional protease that regulates several key biological processes. For example, thrombin is among the most potent of the known platelet activators. In addition, thrombin is essential for the cleavage of fibrinogen to fibrin to initiate clot formation. These two elements are involved in normal hemostasis but in atherosclerotic arteries can initiate the formation of a thrombus, a major factor in pathogenesis of vasoocclusive conditions such as myocardial infarction, unstable angina, nonhemorrhagic stroke and reocclusion of coronary arteries after angioplasty or thrombolytic therapy. Thrombin is also a potent inducer of smooth cell proliferation and may therefore be involved in a variety of proliferative responses such as restenosis after angioplasty and graft-induced atherosclerosis. In addition, thrombin is chemotactic for leukocytes and may therefore play a role in inflammation. (Hoover, R. J., et al. Cell (1978) 14:423; Etingin, O. R., et al., Cell (1990) 61:657.) These observations indicate that inhibition of thrombin formation or inhibition of thrombin itself may be effective in preventing or treating thrombosis, limiting restenosis and controlling inflammation.
The formation of thrombin is the result of the proteolytic cleavage of its precursor prothrombin at the Arg-Thr linkage at positions 271-272 and the Arg-Ile linkage at positions 320-321. This activation is catalyzed by the prothrombinase complex, which is assembled on the membrane surfaces of platelets, monocytes, and endothelial cells. The complex consists of Factor Xa, which is secreted by the liver as a 58 kd precursor and is converted to the active form, Factor Xa, in both the extrinsic and intrinsic blood coagulation pathways. It is known that the circulating levels of Factor X, and of the precursor of Factor Va, Factor V, are on the order of 10.sup.-7 M. There has been no determination of the levels of the corresponding active Factors Va and Xa.
The complete amino acid sequences of human Factor X and Factor Xa are known, and are as described by Davie, E. W., in Hemostasis and Thrombosis, Second Edition, R. W. Coleman et al., eds. (1987) p. 250. Factor X is a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family, which also includes Factors VII and IX, prothrombin, protein C and protein S (Furie, B., et al., Cell (1988) 53:505).
The mature Factor X protein is preceded by a 40-residue pre-pro leader sequence which is removed during intracellular processing and secretion. The mature Factor X precursor of Factor Xa is then cleaved to the two-chain form by deletion of the three amino acids RKR between the light chain C-terminus and activation peptide/heavy chain N-terminus. Finally, the two chain Factor X is converted to Factor Xa by deletion of the 52 amino acid "activation peptide" sequence generating a light chain of 139 residues and a heavy chain of 254 residues. These are linked through a single disulfide bond between position 128 of the light chain and position 108 of the heavy chain. The light chain contains the Gla domain and an epidermal growth factor-like domain; the protease activity resides in the heavy chain and involves the histidine at position 42, the aspartic at position 88, and a serine at position 185.
Bovine Factor X has also been studied, and the amino acid sequence of bovine Factor X has been reported by Titani, K., Proc Natl Acad Sci USA (1975) 72:3082-3086. The activation peptide of bov
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Sinha Uma
Wolf David L.
COR Therapeutics Inc.
Johnson Nancy A.
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