Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-08-27
1999-09-07
Jacobson, Dian C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514822, 530300, 530324, 530384, 536 235, A61K 3817, A61K 3836, C07K 14435, C07K 14745
Patent
active
059487593
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with peptide reagents and compositions thereof which reduce blood clot formation.
Blood clotting relies upon a series or cascade of activating reactions to produce the ultimate fibrin clot. The cascade leading to fibrin formation may be triggered initially in two different ways--by contact with abnormal surfaces (the "intrinsic pathway") or by traumatization of blood vessels which causes secretion of the lipoprotein known as "tissue factor" or TF (the "extrinsic pathway"). The present invention is primarily concerned with the extrinsic blood clotting pathway.
Coagulation factor VII(FVII) is a plasma glycoprotein of M.sub.r =50,000 consisting of a single polypeptide chain with 406 amino acid residues (F. S. Hagen et al., Proc. Natl. Acad. Sci. USA, 1986, 83: 2412-2416; P. J. O'Hara et al., Proc. Natl. Acad. Sci. USA, 1987, 84: 5158-5162). The zymogen form is converted to the fully enzymatically active form FVII.sub.a, by factor X and other coagulation proteases through hydrolysis of a single peptide bond Arg.sup.152 -Ile.sup.153. This results in formation of an enzyme with two polypeptide chains which are held together by a single disulphide bond. The light chain of 152 amino acid residues contains at its amino terminal part the .gamma.-carboxy-glutamic acid (Gla) domain, followed by two epidermal growth factor-like domains (EGF-1 and EGF-2). The heavy chain consists of 254 residues and contains the serine protease catalytic domain. The function of FVII.sub.a is activation of factor X (FX) by complexation with tissue factor (TF) in the presence of Ca.sup.2+ on a phospholipid membrane surface. Activation of FX to FX.sub.a leads to formation of blood clots by the extrinsic pathway. Additionally, the complex FVII.sub.a /TF can activate factor IX to factor IX.sub.a and lead to clotting through the intrinsic pathway.
Activation of the extrinsic pathway for blood clot formation is the primary event leading to fibrin formation and is thus of prime importance in the pathogenesis of arteriosclerotic lesions and in reocclusion and restenosis following endarterectomy. One way of providing potential therapeutic agents capable of preventing the primary event in blood clot formation through the extrinsic pathway would thus be to identify peptides derived from the primary structure of FVII which are capable of inhibiting the complex formation between FVII, TF and FX, which is necessary for FX activation.
Comparatively little is known about the mechanism and sites of interaction of FVII with TF and FX at the molecular level. Nevertheless, a number of FVII-derived peptides have been identified which possess some inhibitory activity with respect to FX activation and which are not inhibitors of the enzymatic activity of FVII.sub.a. Peptides corresponding to sequence portions between the Gla and EGF-1 domains as well as from the catalytic domain, were disclosed in WO 9107432 (Board of Regents, The University of Texas System). A particular peptide from the EGF-2 domain, as well as another peptide from the heavy chain were disclosed in WO 9003390 (Corvas, Inc.). Furthermore, we have disclosed in a co-pending application (PCT/GB94/01315) certain small peptides from the EGF-1 and mainly from the EGF-2 domains. In general the literature suggests that the Gla domain, EGF-1 domain and certain parts of the heavy chain are important in the recognition of FX and TF by FVII (P. Wildgoose et al., Proc. Natl. Acad. Sci. USA, 1990, 87: 7290-7294; W. Ruf et al., J. Biol. Chem., 1991, 266: 15719-15725; A. Kumar et al., Eur. J. Biochem., 1993, 217: 509-518; S. Higashi et al., J. Biol. Chem., 1994, 269: 18891-19989).
We have investigated the EGF-2 domain of FVII and its role in protein-protein interactions involving FVII. The arrangement of the three disulphide bonds present in the EGF-2 domain of FVII is believed to follow a general pattern for proteins containing EGF-like domains and for epidermal growth factor itself (H. Gregory, Nature, 1975, 257: 325-327). For the FVII EGF-2 domain this corresponds to the
REFERENCES:
Kazama et al., J. Biol. Chem., vol. 268, No. 22, Aug. 5, 1993, pp. 16231-16240.
Fischer Peter
Husbyn Mette
Orning Lars
Jacobson Dian C.
Nycomed Imaging AS
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