Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-02-28
1998-01-20
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514822, 530350, 530380, 530855, 530858, 424532, 424537, 424550, A61K 3800, C07K 100
Patent
active
057101310
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with a new protein acting as strong inhibitor of collagen-stimulated platelet activation and aggregation and, above all, having a capacity to prevent interactions between collagen and von Willebrand's factor.
Normal hemostasis in humans is regulated by a complex series of interrelated mechanisms involving both cellular and humoral biochemical components. The biochemical pathway involves injury to intact endothelial cells, stimulation of platelets and activation of coagulation mechanisms. When a vessel wall is damaged, one of the first events is the exposure of subendothelium to the blood. Subendothelial collagen is thought to be one of the very first stimuli that lead to adhesion of platelets, followed by shape change, aggregation and thrombus formation.
Therefore therapeutic intervention at the level of platelet adhesion and/or platelet aggregation is useful for the prevention or treatment of most thrombotic disorders.
It is known that leech salvia contains several agents capable of inhibiting platelet aggregation:
Thus, hirudin is a well known compound (Merck Index 1983, No. 4613; FEBS Lett. 165, 180 (1984)). Hirudin prevents thrombin-induced platelet aggregation by binding to thrombin in a 1:1 stoichiometric complex. This in turn inhibits thrombin-catalysed conversion of fibrinogen to fibrin.
A low molecular weight receptor-mediated platelet activating factor antagonist derived from saliva of Hirudinidae having inhibitory activity against platelet aggregation induced by aggregation agents such as PAF-acether is disclosed in EP-A-0348208.
A collagenase which specifically degrades collagen by means of hydrolytic scission of peptide bonds in helical regions of the collagen molecule is disclosed in WO 87/00860.
The medicinal leech (Hirudo medicinalis) uses not only hirudin to prevent thrombus formation at the site of a bite. A very pronounced characteristic of a bite from this leech is prolonged bleeding for more than 10 up to 24 hrs, whereas hirudin appears to be washed out of the wound within 15 to 30 min. Therefore other principles apart from hirudin must be responsible for this effect.
Recently a protein from Hirudo medicinalis was described (WO 92/07005) having a molecular weight of 65 kD and termed "Calin", which is able to prevent collagen-stimulated platelet aggregation.
Another low molecular (16 kD) inhibitor of collagen-induced platelet aggregation, termed LAPP, was found in Haementeria officinalis (EP-A-0480651).
None of these proteins have been shown to affect the important feature of von Willebrand's factor (vWF) mediated platelet adhesion.
This factor is a complex multimeric glycoprotein that plays an essential role in platelet function. It is required for normal platelet adhesion to exposed subendothelium and for normal platelet plug formation at sites of vascular injury.
The function of vWF is particularly important in vessels of small caliber, where conditions of high wall shear rate prevail. It is now recognized that the mechanisms underlying vWF function comprise interaction with components of the subendothelium as well as with specific receptors on the platelet membrane (Ruggeri et al., 1992, Meth. Enz. 215, 263-275).
Therefore, interference of a corresponding protein with vWF would provide an additional advantage in therapeutic uses.
Now it has been found that a new protein having a molecular weight about 15 kD acts as strong inhibitor of collagen-stimulated platelet aggregation and adhesion and, above all, prevents interactions between collagen and vWF.
Therefore, it is an object of the present invention to provide a substantially pure protein having a capacity to inhibit collagen-stimulated platelet aggregation and to prevent interactions between collagen and vWF, obtainable from the saliva of the medicinal leech Hirudo medicinalis.
The new protein according to the invention has a molecular weight of 14-15.5 kD, preferrably of 14.5-15.0 (dependent oh the used methods) and prevents interactions between collagen and vWF. In contrast to these results, t
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Journal of Biological Chemistry, vol. 267, No. 10, 5 Apr. 1992 (Baltimore, Maryland, pp. 6893-6898.
Orevi et al, Prostaglandins, vol. 43, pp. 483-495, 1992.
Harsfalvi et al, Blood, vol. 85, No. 3, pp. 705-711, Feb. 1, 1995.
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Hemberger Jurgen
Melzer Guido
Merck Patent Gesellschaft mit beschrankter Haftung
Mohamed Abdel A.
Tsang Cecilia
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