Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1986-08-06
1988-08-30
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, A61K 3743, C07K 710
Patent
active
047677422
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to hirudin-PA and its derivatives, a process for manufacturing these substances, pharmaceuticals that contain these substances, and the use of these substances.
BACKGROUND OF THE INVENTION
Several substances have already been extracted from medicinal leeches (hirudo medicinalis) such as polypeptides that act as proteinase inhibitors and which have, in part, an antithrombin action. In the literature that deals with these substances, a distinction is drawn between the so-called eglines and hirudins. Two eglines are described in DE-PS No. 28 08 396. The extraction of crude hirudin is described in Die Pharmazie, Number 36, 1981, pages 653-660 and in Methods in Enzymology, Volume 45, 1976, pages 669-678. The complete amino acid sequence is known from FEBS 1104 (Federation of European Biochemical Societies, Volume 165, 1984, pages 180-184).
SUMMARY OF THE INVENTION
Most surprisingly, it has now been found that crude hirudin contains another component that is pharmacologically active.
For this reason, the present invention undertakes the examination of leech extracts for new pharmacologically effective substances, in particular the hirudin components of leech extracts more precisely for new substances.
According to the present invention, the solution to this task lies in the preparation of new hirudin components, designated hirudin-PA, their decomposition products, and the desulfated derivatives therefrom.
The present invention relates to hirudin-PA of formula I: ##STR1## the derivatives of these substances, shortened at the N-terminus by up to 2 amino acids and at the C-terminus by up to 17 amino acids as well as the desulfated derivatives, in which, in the above formula I: (i) the sulfate ester group at the phenolic hyroxyl of the tyrosin group in position 64 is missing, or (ii) the sulfate ester group described at (i) and the latter or the two last amino acids D, E (in position 66 or 66+65) are missing, and the pharmaceutically useful salts thereof.
A preferred embodiment are hirudin-PA and its derivatives of formula I, the amino acid chain at the N-terminus being shortened by the sequence I or IT.
A further preferred embodiment are hirudin-PA and its derivatives wherein the amino acid chain at the C-terminus is shortened by the sequence: ##STR2##
Especially preferred is hirudin-PA of the formula I ##STR3## and its sulfated derivatives as defined above.
In the preceding formulae the quoted letters symbolize the proteinogenic amino acids that are peptidically linked, these letters corresponding to the IUPAC nomenclature. The salts of these proteins are also the object of the present invention.
The hirudin-PA according to the present invention consists of a total of 66 amino acids; its molecular weight is 7087; its specific antithrombin activity is 680-720 IU/mg and the complex with thrombin has the dissociations constant Ki=4.times.10.sup.-11 M.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the yields of PTH amino acids of the oxidized hirudin-PA;
FIG. 2 is a graph showing the yields of PTH amino acids of tryptic peptide TR 16;
FIG. 3 is a time diagram for the CPY catalyzed liberation of the amino acids of the C-terminus of hirudin-PA; and
FIG. 4 shows the complete sequence for hirudin-PA.
DETAILED DESCRIPTION OF THE INVENTION
Hirudine-PA and its derivatives are structurally very similar to the already known hirudin. However, at several important places on the protein chain, particularly at the beginning and at the end, the products according to the present invention differ in a characteristic manner from the sequence of the known hirudin. This results in further differences that are of great practical significance. The tertiary structure of these polypeptides is stabilized by three disulfide bridges. In hirudin-PA the strongly acid sulfate monoester group on the phenolic hydroxyl of the tyrosin group in position 64 is conspicuous; this can be represented by the following partial-structure formula: ##STR4##
This grouping is also pre
REFERENCES:
Dodt et al., Chemical Abstracts, vol. 105, No. 167762y (1986).
Petersen et al., Chemical Abstracts vol. 85, No. 105932p (1976).
Chang, Chemical Abstracts vol. 100, No. 152937g (1984).
Dodt et al., Chemical Abstracts vol. 100, No. 152937g (1984).
Dodt Johannes
Fink Ernst
Fritz Hans
Seemuller Ursula
Chan Christina
Kight John
Plantorgan-Werk Heinrich G. F. Christensen, KG
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