Platelet aggregation-inhibiting peptides

Details Platelet aggregation-inhibiting peptides Platelet aggregation-inhibiting peptides

1994-05-06

1996-03-12

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 8, 530322, 530329, 530330, A61K 3804, C07K 700

Patent

active

054986010

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel peptides and the like having an inhibitory action on platelet aggregation, and platelet aggregation-inhibiting agents, blood coagulation-inhibiting agents for extracorporeal circulation, cell adhesion-inhibiting agents, tumor metastasis-inhibiting agents and agents for protecting platelet preparations for blood transfusion which comprise the novel peptides or the like as active ingredients as well as platelet preparation packs for blood transfusion which comprise the novel peptides in the platelet preparations for blood transfusion in the packs.


BACKGROUND ART

Platelets play an important role in hemostasis by adhering to the surface of a damaged blood vessel.
However, it is known that platelet aggregation is primarily responsible for the formation of thrombus and that the formed thrombus obstructs a blood vessel. This obstruction prevents the adequate supply of oxygen and nutrients to tissues and organs and thereby causes ischemic diseases in circulatory organs as represented by myocardial infarction and cerebral infarction. At present, the mortality rates of these ischemic diseases follow that of cancer, which has become a significant social problem.
When medical treatments involving the extracorporeal circulation of blood, as exemplified by the use of an artificial heart and lung during surgical operations and renal dialysis for patients with renal failure, are conducted, blood coagulation may be caused by the activation and aggregation of platelets, which greatly disturb the performance of such treatments.
Thus, the prevention of thrombus formation and blood coagulation is an important matter in avoiding the occurrence of ischemic diseases or in safely conducting extracorporeal circulation.
Platelets are activated by the binding, to receptors on a platelet membrane, of thrombin present in plasma, connective tissue proteins such as collagen present in subendothelial tissues that may become exposed by damage to a blood vessel and other substances. Platelets are also activated by the binding of released adenosine diphosphate (ADP), adrenaline, serotonin, thromboxane (TX) A2 and the like to membrane receptors in a manner like autosecretion. Two kinds of glycoprotein units which compose a fibrinogen receptor are presented on the cell surface and associated to form a receptor complex (gpIIbIIIa), whereby aggregation via a fibrinogen bridge is induced.
Patients with thrombasthenia characterized by congenital absence of gpIIb and gpIIIa do not have a capability for platelet aggregation. Therefore, it is clear that the binding of the gpIIbIIIa complex to fibrinogen is essential to platelet aggregation (Rouslahti et al., Science, 238, 491 (1987)).
Attempts have been made to prevent thrombus formation by the inhibition of platelet aggregation utilizing the properties of the gpIIbIIIa complex. For example, Coller et al. reported that an F(ab').sub.2 fragment of a monoclonal antibody against the gpIIbIIIa complex has a strong inhibitory action on platelet aggregation and verified that a platelet aggregation-inhibiting agent could be developed utlizing this action (Blood, 68, 783, (1986)).
Although it is recognized that the monoclonal antibody has the potential as a therapeutic agent for inhibiting platelet aggregation, there is an apprehension for the possible production of antibodies against the monoclonal antibody by its repeated administration, since it is in itself a large protein.
Therefore, it has been desired to develop platelet aggregation-inhibiting agents containing as active ingredients non-immunogenic small compounds that have the properties of antagonists to the gpIIbIIIa complex.
Studies on the binding of fibrinogen to the gpIIbIIIa complex have been conducted aggressively. These studies started with the finding of arginine-glycine-aspartic acid (RGD) as an amino acid sequence common to cell adhesive molecule by a series of studies conducted by Ruoslahti et al. (Ruoslahti et al., Nature 309, 30-33 (1984)). The study of receptors recognizing the

REFERENCES:
Ruggeri, Z. et al. (1986) Inhibition of platelet function with synthetic peptides designed to be high-affinity antagonists of fibrinogen binding to platelets. Proc. Natl. Acad. Sci. USA 83, 5708-5712. See entire article, especially Tables 1 and 2 on p. 5710.

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