Patent
1993-06-14
1995-12-12
Wityshyn, Michael G.
A61K 3843, C07K 1400
Patent
active
054750890
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a thrombolytic agent obtained from staphylokinase which are effective for curing myocardial infarction, walnut brain, arteriosclerosis and the like, by cleaving therefrom moieties which do not affect its activity.
BACKGROUND ART
Staphylokinase (hereinafter abbreviated as SAK) has no protease activity in itself, but is a kind of plasminogen activator similar to streptokinase (hereinafter abbreviated as SK) in that its complex with plasminogen or plasmin activates plasminogen. SAK has a molecular weight of about 15,000 and a size which is not greater than 1/3 of the size of SK. Since the genes have been cloned and their DNA sequences have been elucidated, it is considered that SAK is an appropriate substance for analyzing the action mechanism on a molecular level. The inventors of this application have proposed a method for collecting SAK accumulated in coliform bacilli which are integrated with SAK genes and cultivated (Japanese Patent Laid-open No. 58-67181). A major proportion of SAK obtained by the method is composed of a peptide which consists of 136 amino acid residues SEQ ID NO: 1 (Sako, T., Eur. J. Biochem., 149, 557-563(1985)).
It has been found that the action mechanism of SAK is different from that of SK. Especially, it has been confirmed that unlike SK, SAK has such a characteristic feature that the activity is increased in the presence of fibrin (i.e. fibrin specificity) and, thus, functions as a good thrombolytic agent (Japanese Patent Laid-open No. 63-90252). Also, in order to improve the delayed reactivity of SAK, there has been proposed a thrombolytic agent in which a complex of SAK and plasminogen (or fibrin) is preformed (Japanese Patent Laid-open No. 1-13044).
SAK composed of a peptide which consists of 136 amino acid residues obtained by the above-mentioned method is advantageous in that its molecular weight is smaller than other thrombolytic agents hitherto employed, ensuring good penetration into thrombi, coupled with another advantage that mass production by a simple manner is possible. This results in a better economy than in the case of other thrombolytic agents.
Although SAK composed of a peptide which consists of 136 amino acid residues has good characteristics as stated above, a smaller molecular weight is more preferable to prevent the occurrence of problems on antigenicity and dosage, etc.
DISCLOSURE OF THE INVENTION
The object of the present invention is to improve SAK composed of a peptide which consists of 136 amino acid residues, and to provide a thrombolytic agent, which is capable of preventing the occurrence of the problems on the antigenicity or immunogenicity with the reduced dosage.
To accomplish the above object, a thrombolytic agent according to one aspect of the present invention contains a peptide residue having at least an amino acid sequence set forth in SEQ ID NO: 2.
In more detail, according to an embodiment of the present invention, the thrombolytic agent contains as its effective ingredient the peptide residue obtained from SAK by cleaving off a moiety including an amino acid or a peptide which does not affect the activity of said SAK. More preferably, the thrombolytic agent contains as its effective ingredient the peptide residue obtained from said SAK by cleaving off a peptide composed of ten amino acid residues at the N-terminal of said SAK through a treatment process for said SAK with a trypsin protease.
More particularly, it has been found that such a peptide residue as set forth above has the thrombolytic action better than the original SAK.
In the present invention, studies have been made on the cleaving, from SAK composed of a peptide which consists of 136 amino acid residues, of the moiety having no affect on the activity of SAK by using various types of protease. As a result, it has been found that a peptide (hereinafter referred to simply as SAK-11) which is obtained by cleaving from SAK a peptide consisting of ten amino acids at the N-terminal (i.e. Ser Ser Ser Phe Asp Lys Gly Lys Tyr Lys) is equiv
REFERENCES:
Matsuo Osamu, Blood, vol. 76, No. 5, pp. 295-929, Sep. 1990.
Z. Bakteriol. Infekt. Hyg., I Abt., Suppl. 5, (1976) T. Makino et al., "Studies on Staphylokinase", pp. 539-547.
Biochimica et Biophysica ACTA, vol. 522, (1978), T. Makino "Proteolytic Modification of Staphylokinase", pp. 267-269.
Hashimoto Shusuke
Matsumoto Tsuneo
Matsuo Osamu
Onoue Masaharu
Sakai Masashi
Kabushiki Kaisha Yakul't Honsha
Sayala C.
Wityshyn Michael G.
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