Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1985-02-14
1994-12-20
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530307, 530324, A61K 3702, C07K 710
Patent
active
053746180
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to peptides, pharmaceutical compositions, processes for producing the peptides, genes coding for the peptides, vectors including the genes and host organisms transformed with the vectors, and gene probes and antibodies for use in diagnosis.
BACKGROUND OF THE INVENTION
The calcitonin gene system has been the subject of considerable research in recent years. In particular, studies on rat calcitonin gene expression have demonstrated the generation, by RNA processing, of alternative mRNA species in an apparently tissue specific manner to produce different peptide hormones from a single gene. (Craig R. K. et al (1983) Genetic Engineering 4, 57-125 and Amara et al (1982) Nature 298, 240-244). Each mRNA species encodes a polyprotein cleaved by post translational processing events to yield either rat calcitonin or rat calcitonin gene related peptide (rat CGRP). The rat CGRP is known to be widely distributed in discrete regions of the central and peripheral nervous system where it has been shown to have potent biological activity (Fisher et al (1983) Nature, 305, p 534-536).
In copending European patent applications EP-A1-0070186 and EP-A1-0070675 (R. K. Craig and I. MacIntyre) there are described the production of human calcitonin and a carboxy terminal peptide designated PDN-21 (Katacalcin). Human calcitonin and katacalcin are formed as a polyprotein encoded by the human calcitonin mRNA (Craig et al (1982) Nature, 295, p 345-347).
We have now discovered a region of the human calcitonin gene which is transcribed in human medullary carcinoma cells, and is located distal to the 3' translated region of the human calcitonin mRNA. The region comprises a transcribed intron region, a splice junction, an open reading frame which encodes previously unknown human peptide sequences, and a 3' untranslated region terminating with a tract of poly A residues. One of the peptides is apparently an analogue of rat CGRP, which analogue we refer to hereinafter as human calcitonin gene related peptide (human CGRP).
SUMMARY OF THE INVENTION
According to a first aspect of the invention, we provide human calcitonin gene related peptide.
According to a second aspect of the present invention we provide a peptide having the structure ##STR1##
This novel peptide is formed as part of a polyprotein which is specifically cleaved in vivo within the secretory pathway by proteolytic enzymes which recognise flanking basic amino acid residues. The peptide (which has been designated PAF-37 in accordance with the terminology of Tatemoto and Mutt (1981) PNAS 78 p 6603-6607) has been found to have a potent biological effect in the modulation of cardiovascular function. In particular the peptide has been shown to induce hypotension and to increase heart beat rate and force.
In a second aspect of the invention the peptide is provided for use as a pharmaceutical, preferably for use in treatment of hypertension. It is common, in the post operative stages of major heart surgery (for example in open heart bypass operations), for the patient to react to the stress of the operation by extensive vasoconstriction. This has the effect of increasing the patient's blood pressure, thus straining the heart. The peptide of the invention has been shown to act as a hypotensive agent and to increase the force of heart beat. These combined effects make it of potential use as a post-operative treatment. A large percentage of people suffer from hypertension and it is a strong contributory factor in the high incidence of heart failure. The peptide may be used in the management of hypertension.
In a third aspect of the invention we provide a pharmaceutical composition comprising a peptide of the structure (I) and a pharmaceutically acceptable excipient. Preferably the composition is an injectable composition. The pharmaceutical composition may be contained within, or form part of, a system for the controlled slow release of the composition or the peptide in or into the body. Such a controlled slow release system is of use in
REFERENCES:
Chemical Abstracts vol. 93, 1980 Pt. 218.
"Isolation and Characterization of Human Calcitonin Gene-related Peptide" by H. R. Morris et al, Nature, vol. 308, Apr. 19, 1984, pp. 746-748.
"Calcitonin mRNA Polymorphism: Peptide Switching Associated With Alternative RNA Splicing Events", by M. G. Rosenfeld et al, Proc. Natl. Acad. Sci. USA vol. 79, pp. 1717 to 1721, Mar. 1982, Biochemistry.
"The Construction and Partial Characterization of Plasmids Containing Complementary DNA Sequences to Human Calcitonin Precursor Polyprotein", by N. Allison et al, Biochem. J. (1981) 199, pp. 725-731.
"Partial Nucleotide Sequence of Human Calcitonin Precursor mRNA Identifies Flanking Cryptic Peptides", by Roger K. Criag et al, Nature, vol. 295, 28 Jan. 1982, pp. 345 to 347.
"Alternative RNA Processing in Calcitonin Gene Expression Generates mRNAs Encoding Different Polypeptide Products", by Susan G. Amara et al, Nature, vol. 298, 15 Jul. 1982, pp. 240-244.
Craig Roger K.
Edbrooke Mark R.
Celltech Limited
Lee Lester L.
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