Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Patent
1992-06-04
1997-06-10
Jacobson, Dian C.
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
435212, 4351723, 424 9464, A61K 3748, C12N 968, C12N 1559
Patent
active
056374925
DESCRIPTION:
BRIEF SUMMARY
This invention relates to proteinaceous compounds which can be activated to have fibrinolytic activity or to inhibit blood clot formation. It also relates to nucleic acid (DNA and RNA) coding for all or part of such compounds. In preferred embodiments, the invention relates to plasminogen analogues, their preparation, pharmaceutical compositions containing them and their use in the treatment of thrombotic disease.
Plasminogen is a key component of the fibrinolytic system which is the natural counterpart to the clotting system in the blood. In the process of blood coagulation, a cascade of enzyme activities are involved in generating a fibrin network which forms the framework of a clot, or thrombus. Degradation of the fibrin network (fibrinolysis) is accomplished by the action of the enzyme plasmin. Plasminogen is the inactive precursor of plasmin and conversion of plasminogen to plasmin is accomplished by cleavage of the peptide bond between arginine 561 and valine 562 of plasminogen. Under physiological conditions this cleavage is catalysed by tissue-type plasminogen activator (tPA) or by urokinase-type plasminogen activator (uPA).
If the balance between the clotting and fibrinolytic systems becomes locally disturbed, intravascular clots may form at inappropriate locations leading to conditions such as coronary thrombosis and myocardial infarction, deep vein thrombosis, stroke, peripheral arterial occlusion and embolism. In such cases, the administration of fibrinolytic agents has been shown to be a beneficial therapy for the promotion of clot dissolution.
Fibrinolytic therapy has become relatively widespread with the availability of a number of plasminogen activators such as tPA, uPA, streptokinase and the anisoylated plasminogen streptokinase activator complex, APSAC. Each of these agents has been shown to promote clot lysis, but all have deficiencies in their activity profile which makes them less than ideal as therapeutic agents for the treatment of thrombosis (reviewed by Marder and Sherry, New England Journal of Medicine 1989, 318: 1513-1520). One of the major problems with tPA for the treatment of acute myocardial infarction or other thrombotic disorders is that it is rapidly cleared from the circulation with a plasma half-life in man of around 5 minutes (Bounameaux et al in: "Contemporary Issues in Haemostasis and Thrombosis" vol 1 p5-91, 1985. Collen et al eds, Churchill Livingstone). This results in the need to administer tPA by infusion in large doses. The treatment is therefore expensive and is delayed as the patient has to be hospitalised before treatment can commence. Urokinase, in either the single chain form (scuPA) or the two chain form (tcuPA), has a similar rapid plasma clearance and also requires administration by continuous infusion.
A major problem shared by all of these agents is that at clinically useful doses, they are not thrombus specific as they activate plasminogen in the general circulation. The principal consequence of this is that proteins such as fibrinogen involved in blood clotting are destroyed and dangerous bleeding can occur. This also occurs with tPA despite the fact that, at physiological concentrations, it binds to fibrin and shows fibrin selective plasminogen activation.
Another important shortcoming in the performance of existing plasminogen activators is that re-occlusion of the reperfused blood vessel commonly occurs after cessation of administration of the thrombolytic agent. This is thought to be due to the persistence of thrombogenic material at the site of thrombus dissolution.
An alternative approach to enhancing fibrinolysis has now been devised which is based on the use of molecules activatable to have fibrinolytic activity or to inhibt clot formation. The activation (which may involve cleavage) can be catalysed by one or more endogenous enzymes involved in blood clotting. An advantage of this approach is that thrombus selectivity of fibrinolytic or inhibition of clot formation activity is achieved by way of the thrombus-specific localisation of the acti
REFERENCES:
patent: 5200340 (1993-04-01), Forster et al.
Dawson Keith
Edwards Richard M.
Forman Joan M.
British Biotech Pharmaceuticals
Jacobson Dian C.
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