Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Patent
1991-12-20
1994-10-04
Cashion, Jr., Merrell C.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C07K 700
Patent
active
053527704
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a novel porcine derived physiologically active peptide (CNP) having natriuretic and hypotensive actions, as well as the capability of suppressing the growth of vascular smooth muscle cells.
BACKGROUND ART
Two kinds of peptide hormones, named "atrial natriuretic peptide (ANP)" and "brain natriuretic peptide (BNP)", have recently been isolated from mammalian atria and brains as hormones that regulate the homeostatic balance of body fluid volume and blood pressure. The structures of those peptides and the mechanism of their biosynthesis have been unravelled and their physiological actions are also being unravelled.
ANP was first isolated from the human atrium in three types, .alpha.-type having a molecular weight of ca. 3000 (.alpha.-hANP), .beta.-type of ca. 6000 (.beta.-hANP) and .gamma.-type of 13000 (.gamma.-hANP), and their respective structures were unravelled (Kangawa, K. et al., Blochem. Biophys. Res. Commun., 118, 131, 1984; Kangawa, K. et al., Nature, 313, 397, 1985).
As a result, the following facts have been determined: (1) .alpha.-hANP is a single-stranded peptide that consists of 28 amino acids having a single S-S bond in the molecule; (2) .beta.-hANP is an antiparallel dimer having an S-S bond formed between the molecules of .gamma.-hANP; and (3) .gamma.-hANP is a high-molecular weight protein composed of 126 amino acids, with .alpha.-hANP being contained in the C-terminal portion.
Further, analysis of the cDNA coding for .alpha.-hANP has shown that each of those three types of hANP (.alpha.-, .beta.- and .gamma.-hANP) is biosynthesized from the same precursor protein (Oikawa, S. et al., Nature, 309, 724, 1984). Stated more specifically, those peptides are first biosynthesized in atrial cells as a precursor (pre-hANP) composed of 151 amino acid residues and then, the signal peptide composed of 25 N-terminal residues is cleaved in the Golgi body to produce .gamma.-hANP. Subsequently, the .gamma.-hANP is further cleaved with an enzyme (i.e., subjected to processing) for transformation to .alpha.-hANP, which is secreted primarily into blood. The process of .beta.-hANP synthesis still remains unclear today but most probably it is produced by way of .alpha.-hANP.
Ever since the structure of hANP was first unravelled, the structures of ANPs derived from other mammals have also been studied. And, today, the following knowledge is available: ANPs have similar amino acid sequences over a broad spectrum of mammals ranging from rodents to humans; in particular, .alpha.-type ANP (.alpha.-ANP) has the same amino acid sequence in higher mammals including humans, dogs and pigs; and .alpha.-type ANPs derived from rats and rabbits have entirely the same amino acid sequence as .alpha.-hANP except that the methionine residue in position 12 is replaced by an isoleucine residue (0ikawa, S. et al., Blochem, Biophys. Res. Commun., 132, 892, 1985; Forssmann, W.G. et al., Anat. Embryol., 168, 307, 1983).
When the distribution of ANP in vivo was examined using anti-.alpha.-hANP antisera, it was found that ANP also occurred in the brain, though in small amounts, as well as in the atrium. Further, ANP-containing neurons have been reported to occur in the hypothalamus and pontine tegmentum of the brain (Cantin, M. et al., Itistochemistry, 80, 113, 1984; Saper, C.B., et al., Science, 227, 1047, 1985) and, therefore, it is speculated today that ANP may also work in the brain as a nerve transmitter that participates in the regulation of the cardiovascular system.
Recently, a new peptide that was similar in structure to ANP but that was clearly distinguishable from the latter was isolated and identified from porcine brain and, like ANP, this peptide was verified to have natriuretic and hypotensive actions and hence was named "BNP" (Sudoh, T. et al., Nature, 332, 78, 1988). It was later found that porcine-derived BNP (pBNP) was a single-stranded peptide composed of 26 amino acids having a single S--S bond in the molecule. Further, a cDNA coding for human BNP was isolated and the str
REFERENCES:
Chemical Abstracts, vol. 115, No. 115, 1991.
Tawaragi et al., "Gene and Precursor Structure of Porcine C-type Natriuretic Peptide", Biochemical and Biophysical Research Communications, vol. 172, No. 2, Oct. 30, 1990, pp. 627-632.
Minamino et al., "N-Terminally Extended Form of C-Type Natriuretic Peptide (CNP-53) Identified in Porcine Brain", Biochemical and Biophysical Research Communications, vol. 170, No. 2, 1990, pp. 973-979.
Sudoh et al. Biochem. Biophys. Res. Comm. 168 (1990) 863-870.
Minamino et al. Biochem. Biophys. Res. Commun. 157 (1988) 402-409.
Cashion Jr. Merrell C.
Salata Carol A.
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