Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 6 to 7 amino acid residues in defined sequence
Patent
1985-08-20
1988-06-14
Phillips, Delbert R.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
6 to 7 amino acid residues in defined sequence
530326, 530327, 530328, 530329, 530350, 530399, 530841, C07K 710, A61K 3702, A61K 4900
Patent
active
047512849
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention concerns a new peptide hormone and a process for its preparation.
From electron microscopic investigations, it was known that the right heart auricle (atrium) of the pig contains two different cell types, one of which has the morphology of endocrine cells (secretary granular). By means of morphological and histological investigations of the right atrium, however, no hormone substance, such as that of the type already known in myoendocrine cells of the heart auricle, could be determined. On the other hand, many of the known neuropeptide hormones were ascertained in the heart nerves.
It has now been found that atrium extracts (heart auricle), besides an already described diuretic activity (cf. J. -P. Marie, H. Guillemont, P. Y. Hatt, Pathol. Biol., 24 (1976) (549-554), surprisingly display effects on the ionotropia of the heart muscle itself or influences on the smooth blood vessel musculature, as well as influences on the secretion of perspiration. Furthermore, it was found that these biological actions were caused by a new peptide hormone which, having regard to its actions, has a great clinical and therapeutic importance, especially with regard to the diagnosis and therapy of hypertonia.
Therefore, the subject of the invention is the new peptide hormone cardiodilatin with the N-terminal amino acid sequence: Asn-Pro-Val-Tyr-Gly-Ser-Val-Ser-Asn-Ala-Asp-Leu-Met-Asp-Phe-Lys-Asn-Leu-Le u-Asp-His-Leu-Glu-Asp-Lys-Met-Pro-Leu-Glu-Asp-Glu-Ala-Met-Pro-Pro-Gln-Val-L eu-Ser-Glu-Gln-Asp-Glu-Glu-Val-Gly-Ala-Pro-Leu-Pro-Leu-Leu-Glu-Glu-Val-Pro- Pro-Trp-Thr-Gly-Glu-Val-Asn-Pr of the composition: Asp/Asn 14, Thr 3, Ser 15, Glu/Glu 12, Pro 10, Gly 12, Ala 10, Val 7, Met 4, Ile 1, Leu 15, Tyr 2, Phe 3, Lys 4, His 2, Arg 10, Trp 2, a length of 126 amino acid residues and an isoelectric point I.P. of 6 to 6.5.
Furthermore, it has been found that fragments, especially C-terminal fragments and the fragments of the peptide hormone cardiodilatin present between two Met residues of the peptide chain display the biological activities of cardiodilatin, even though, in part, in weakened form.
Therefore, the subject of the invention are also the fragments of the peptide hormone cardiodilatin present between two Met residues of the peptide chain, such as e.g. the fragment with the amino acid sequence Asp-Phe-Lys-Asn-Leu-Leu-Asp-His-Leu-Glu-Asp-Lys-Hse (1) or the fragment with the amino acid sequence Pro-Leu-Glu-Asp-Glu-Ala-Hse (2 ) and the N-terminal fragment Asn-Pro-Val-Tyr-Gly-Ser-Val-Ser-Asn-Ala-Asp-Leu-Hse, as well as in each case the C-terminal remaining rump sequence of the cardiodilatin 126 shortened by the state homoserine peptides. One obtains these framents by partial cyanogen bromide fissions, whereby the N-terminal shortening of the cardiodilatin leads to separated off fragments which, in each case, end C-terminally with homoserine (Hse). The N-terminal shortened fragments of cardiodilatin formed by fission with arginine-specific endopeptidase also display qualitatively the same biological effectiveness as the parent molecule even though in weakened form.
Furthermore, a series of cardiodilation fragments were prepared either synthetically by Merrifield synthesis or by fission of the cardiodilatin with specifically-splitting proteases and investigated. The Merrifield synthesis was thereby so carried out that, beginning at the C-terminal end, the amino acid chain was, in each case, lengthened by two amino acids, split off, investigated and, according to the same principle, lengthened by a further two amino acids. This process was repeated as often as was necessary for the fragments obtained and more closely defined further below.
The fragments prepared display an interesting biological activity, namely, they are suitable for the formation of antibodies which are able to recognise the whole cardiodilatin and, therefore, can also be used for its detection in the scope of an immune assay. There are suitable not only the numerous known embodimental forms of the RIA (radio-immune assay) but also of the E
REFERENCES:
patent: 4604234 (1986-08-01), Fujii et al.
patent: 4638050 (1987-01-01), Aoki et al.
patent: 4675382 (1987-06-01), Murphy
Forssmann et al, "The Right Auricle of the Heart is an Endocrine Organ", tomy and Embryology (1983) 168:307-313.
Lazure et al, FEBS Letters, vol. 172, No. 1, pp. 80-86, "Atrial Pronatriodilatin: A Precursor for Natriuretic Factor and Cardiodilatin".
Nakayama et al, Nature, vol. 310, No. 3979, pp. 699-701, "mRNA Sequence for Human Cardiodilatin-Atrial Natriuretic Factor Precursor and Regulation of Precursor mRNA in Fat Atria".
Nutter Nathan M.
Organogen Medizinisch-Molekularbiologische Forschungsgesellschaf
Phillips Delbert R.
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