Thrombin generation inhibitors

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 8 to 10 amino acid residues in defined sequence

Reexamination Certificate

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Details

C530S329000, C530S330000, C530S331000, C530S332000, C530S380000, C514S015800, C514S016700, C514S017400, C514S018700

Reexamination Certificate

active

07074892

ABSTRACT:
Peptides derived from amino acids 307 to 356 of the human blood coagulation factor Va are provided. Such peptides comprise: i) a length of between 3 and 50 amino acids, ii) a minimum of 3 contiguous amino acids from the 307–356 heavy chain region of factor Va, excluding peptide segments comprising amino acids 311 to 325 and amino acids 321 to 335, iii) optional additional amino acids at one or both ends of the contiguous amino acids such that the entire peptide is at least 60% identical to a sequence within 307 to 356 of factor Va, and iv) have an IC50of between 50 nM to 500 μM for inhibition of prothrombinase. The present invention also provides a pharmaceutical composition comprising one or more prothrombinase-inhibiting peptide segments. The present invention also provides administration of the pharmaceutical composition to human subjects for the purpose of preventing thrombotic disorders.

REFERENCES:
patent: 6165737 (2000-12-01), Wang et al.
patent: 6703364 (2004-03-01), Kalafatis et al.
patent: 9916529 (1999-07-01), None
patent: WO 9500633 (1995-01-01), None
Duve et al. Isolation, sturcture, and activity of -Phe-Met-Arg-Phe-NH2 neuropeptide ( designated calliFNMRamides) from the blowflyCalliphora vomitoria. Proceedings of the National Academies of Science, USA. Mar. 1992. vol. 89, pp. 2326-2330.
“Peptide inhibitors expressedin vivo” by Kamb, et al.,Curr. Opin. Chem. Biol.Feb. 2001; 5(1):74-7.
“Characterization of the Molecular Defect in Factor VR506Q” by Kalafatis, et al.,The Journal of Biological Chemistry, vol. 270, No. 8, Feb. 24, 1995, pp. 4053-4057.
“The Regulation of Clotting Factors” by Kalafatis, et al.,Critical Reviews in Eukaryotic Gene Expression, 7(3):241-280(1997).
“Role of the Membrane in the Inactivation of Factor Va by Activated Protein C*” by Kalafatis, et al.,The Journal of Biological Chemistry, vol. 268, No. 36, Dec. 25, 1993, pp. 27246-27257.
“Proteolytic alterations of membrane-bound factor Va during inactivation by plasmin” by Kalafatis, et al., 1997, Abstract No. PS-2503 at scientific meeting.
“The Role of the Membrane in the Inactivation of Factor Va by Plasmin” by Kalafatis, et al.,The Journal of Biological Chemistry, vol. 276, No. 21, May 25, 2001, pp. 18614-18623.
“Binding Site for Blood Coagulation Factor Xa Involving Residues 311-325 in Factor Va*” by Kojima, et al.,The Journal for Biological Chemistry, vol. 273, No. 24, Jun. 12, 1998, pp. 14900-14905.
“Proteolytic processing of human coagulation factor IX by plasmin” by Samis, et al.,Blood, vol. 95, No. 3, Feb. 1, 2000, pp. 943-951.
“Inhibitory Mechanism of the Protein C Pathway on Tissue Factor-Induced Thrombin Generation” by van't Veer, et al.,The Journal of Biological Chemistry, vol. 272, No. 12, Mar. 21, 1997, pp. 7983-7994.
“Importance of individual activated protein C cleavage site regions in coagulation Factor V for Factor Va Inactivation and for Factor Xa activation” by Heeb, et al.,Eur. J. Biochem., 260, 64-75(1999).
“The Structure and Function of Murine Factor V and Its Inactivation by Protein C” by Yang, et al.,Blood, vol. 91, No. 12, Jun. 15, 1998, pp. 4593-4599.

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