Superior thrombomodulin analogs for pharmaceutical use

Details Superior thrombomodulin analogs for pharmaceutical use Superior thrombomodulin analogs for pharmaceutical use

1993-11-22

1995-11-14

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 8, A61K 3514

Patent

active

054666686

ABSTRACT:
The present invention relates to the use of analogs of thrombomodulin ("TM") that have the ability to enhance the thrombin-mediated activation of protein C but which have a significantly reduced ability to inhibit the direct procoagulant activities of thrombin, such as, for example, thrombin-mediated conversion of fibrinogen to fibrin. These analogs are useful in, for example, antithrombotic therapy. Novel proteins, nucleic acid gene sequences, pharmaceuticals and methods of inhibiting thrombotic activity are disclosed. Included are methods for increasing the circulating half life of the proteins.

REFERENCES:
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Bourin et al., "Functional Domains of Rabbit Thrombomodulin", PNAS, vol. 83, pp. 5924-5928 (1986).
Lin et al., "Modulation of Glycosaminoglycan . . . Thrombomodulin", J. Biol. Chem., pp. 25021-25030 (1991).
Esmon, N. L., et al., "Isolation of a Membrane-bound Cofactor for Thrombin-catalyzed Activation of Protein C," J. Biol. Chem. 257:859-864 (1982).
Salem, H. H, et al., "Isolation and Characterization of Thrombomodulin from Human Placenta," J. Biol. Chem. 259:12246-12251 (1984).
Jackman, R. W., et al., "Characterization of a thrombomodulin cDNA reveals structural similarity to the low density lipoprotein receptor," PNAS 83:8834-8838 (1986).
Jackman, R. W., et al., "Human thrombomodulin gene is intron depleted: Nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control," PNAS 84:6425-6429 (1987).
Wen, D., et al., "Human Thrombomodulin: Complete cDNA Sequence and Chromosome Localization of the Gene," Biochemistry, 26:4350-4357 (1987).
Kurosawa, S., et al., "A 10-kDa Cyanogen Bromide Fragment from the Epidermal Growth Factor Homology Domain of Rabbit Thrombomodulin Contains the Primary Thrombin Binding Site," J. Biol. Chem. 263:5993-5996 (1988).
Zushi, M., et al., "The Last Three Consecutive Epidermal Growth Factor-like Structures of Human Thromobomodulin Comprise the Minimum Functional Domain for Protein C-activating Cofactor Activity and Anticoagulant Activity," J. Biol. Chem. 264(18):10351-10353 (1989).
Bourin, M. C., et al., "Functional domains of rabbit thrombomodulin," Pro. Natl. Acad. Sci. USA 83:5924-5928 (1986).
Preissner, K. T., et al., "Domain Structure of the Endothelial Cell Receptor Thrombomodulin as Deduced from Modulation of Its Anticoagulant Functions," J. of Biol. Chem. 265-(9):4915-4922 (1990).
"Prevention of Venous Thrombosis and Pulmonary Embolism," Consensus Development Conference Statement, NIH 6(2):1-23 (Mar., 1986).
Ishii, H., et al., "Thrombomodulin Is Present in Human Plasma and Urine," J. Clin. Inv. 76:2178-2181 (1985).
Stearns, D. J., et al., "Microthrombomodulin: Residues 310-486 from the Epidermal Growth Factor Precusor Homology Domain of Thrombomodulin will Accelerate Protein C Activation," J. Biol. Chem. 264:3352-3356 (1989).

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