Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1988-12-05
1993-12-07
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 12, 514 21, 530324, 530326, 930 10, A61K 3702, C07K 1300
Patent
active
052683591
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present inventions relates to human tachykinins, their precursors and their production by recombinant DNA technology.
The abbreviations used herein are as follows:
2. Description of Related Art Including Information Disclosed under 35 C.F.R. .sctn..sctn.1.97-1.99.
The tachykinins are a family of small peptides, present in the brain and peripheral tissues, which play important roles as neurotransmitters and as hormones. The tachykinins are characterised by a common C-terminal amino acid sequence, -Phe-X-Gly-Leu-Met-NH.sub.2, wherein X is a hydrophobic or aromatic residue [Erspamer, V., Trends in Neuroscience, 4, 267-269, 1981].
The first tachykinin found in mammals is known as substance P, which is though to be involved in the transmission of painful stimuli in the spinal cord. It is also released from sensory nerves in the skin and is thought to play a role in the inflammatory response.
Subsequently, other tachykinins, known as neurokinin A and neurokinin B were reported [Kimura, S., Oada, M., Sugita, Y., Kanazawa, I. and Munekata, E., Proc Jap. Acad. Series B, 59, 101-104, 1983], and it has recently been shown [Tatemoto, K., Lundberg, J. M., Jornvall, H and Mutt, V., Biochem. Biophys. Res. Comm., 128, 947-953, 1985] that in the porcine central nervous system, there is a larger tachykinin, known as neuropeptide K.
It has been shown [Nawa, H., Hirose, T., Takashima, H., Inayama, S. and Nakanishi, S., Nature, 306, 32-36, 1983] that in bobine brain substance P is derived from one of two larger polypeptide precursors, known as alpha- and beta-bovine preprotachykinin (bPPT). It has been shown that the mRNAs encoding alpha- and beta-bPPTs are derived from a single bPPT gene as a result of tissue specific RNA splicing [Nawa, H., Kotani, H and Nakanishi, S., Nature 312, 729-734, 1984]. It has been shown that bovine neurokinin A is derived from beta-bPPT but cannot be derived from alpha-bPPT.
Thus, it has been shown that residues 58 to 68 and 98 to 107 of beta-bPPT correspond to bovine substance P and bovine neurokinin A. Moreover it has been shown that residues 72 to 107 correspond to the sequence of bovine neuropeptide K.
SUMMARY OF THE INVENTION
The present invention is based on the observation that certain human carcinoid tumours may produce large quantities of ectopic substance P and that these tumour cells might therefore provide a source of human substance P mRNA. During this investigation, it was discovered that human substance P was part of a precursor polypeptide similar to bovine beta-PPT. This polypeptide is referred to herein as hPPT. The existence of a human (h) PPT polypeptide had not previously been demonstrated. hPPT mRNA was discovered to be closely homologous to beta-bPPT mRNA, and it was therefore appreciated that this could provide a source not only of human substance P, but also of other human tachykinins.
Therefore the present invention provides human PPT, human tachykinins derived therefrom, cDNA sequences coding therefor, plasmids containing these sequences, and methods for their production using recombinant DNA technology.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a human DNA sequence containing nucleotides numbered 1 to 1021; and
FIGS. 2(a) to (c) shows schematically the restriction enzyme maps of segments excised from 2 plasmids designated 8.216 and E293.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present inventors have discovered that a human PPT gene encodes a human PPT polypeptide which contains sequences identical to bovine substance P and neuropeptide K and porcine neurokinin A.
Therefore the present invention provides a DNA consisting of or containing the human nucleotide sequence 1 to 1021 as shown in FIG. 1, a DNA consisting of or containing the human nucleotide sequence 1 to 260 as shown in FIG. 1 and a DNA consisting of or containing the human nucleotide sequence 148 to 1021 as shown in FIG. 1.
The invention also provides fragments of the DNA sequences defined above.
Further, the present invention provid
REFERENCES:
Tatemoto et al, Chemical Abstracts, 103, No. 5, 1985, p. 53, abst. No. 32420y.
Nawa et al, Nature, 306, 32-36, 1983.
Harmer et al., FEBS Letters, 208, No. 1, Nov. 1986, pp. 67-72.
Harmar Anthony J.
McKeown Ann
Pascall John
Medical Research Council
Moezie F. T.
White John P.
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