Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1986-11-10
1989-06-20
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
514 12, 530309, 530324, A61K 4900, A61K 3724, C07K 732
Patent
active
048407852
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a mammal intestinal hormone precursor related to the hormone secretin which stimulates pancreatic secretion.
Secretin is an intestinal hormone formed by the mucosa of the upper portion of the small intestine, which stimulates the secretion of water and bicarbonate from the pancreas. The structure of porcine secretin has been known for some time and it has been isolated from porcine intestine and has been found to be constituted by a peptide composed of 27 amino acid residues (Mutt, V., Jorpes, J.E. and Magnusson, S. (1970) Eur.J.Biochem., 15, 513-519). Moreover, it has been found that bovine and porcine secretins are identical but that they are marked different from chicken secretin (Carlquist, M., Jornvall, H. and Mutt, V. (1981) FEBS Lett., 127, 71-74). The C-terminal amino acid residue of secretins (valine in porcine/bovine, methionine in chicken) is, as in many other hormonally active peptides, amidated.
In accordance with the present invention variant forms of secretins which are not amidated at its C-terminal residue but instead have a C-terminal residue of glycine have now been found. These variants which can be considered as proforms are precursors to the natural secretins possess high secretin-like bioactivity.
Thus, according to the present invention there is provided a mammal intestinal hormone precursor having the following peptide structure: His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-L-M-Ala-Arg-Leu-Gl n-Arg-Leu-Leu-Gln-Gly-Leu-Val-Gly-N-O, wherein L is Glu or Asp, M is Gly or Ser, and N and O are selected from Lys and Arg.
It can be seen from this structure that it contains 30 amino acid residues corresponding to a natural secretin molecule extended by three amino acid residues.
In the hormone precursor corresponding to the human secretin L is Glu and M is Gly, whereas in the non-human counterpart L is Asp and M is Ser.
In regard to the C-terminal amino acid residues it is preferred that one of N and M is Lys and the other one is Arg.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawigns
FIG. 1 is a reverse-phase chromatogram involving a first step purification of the secretin variant or precursor.
FIG. 2 is a chromatogram from the second step purification of the secretin variant or precursor after an ion exchange HPLC-step.
FIG. 3 is a chromatogram of the tryptic fragments of the purified peptide and of secretin.
FIG. 4 is another chromatogram of the tryptic fragments of the purified peptide and of secretin.
It has been found that the secretin precursors according to this invention are at least as potent as natural secretins in stimulating the secretion of bicarbonate by the pancreas of the anesthetized cat (Mutt, V. and Soderberg, U. On the assay of secretin. Ark.Kem. 15, 63-68, 1959).
In the instant disclosure the abbreviations used for characterizing the amino acids and their residues are the traditional ones as found for example in the textbook Organic Chemistry, second edition, Ralph J. Fessenden & Joan S. Fessenden, Willard Grant Press, Boston, Mass., pages 852 and 853.
In the same way as the known natural secretins find diagnostic uses the secretin precursors according to this invention are highly useful in determining pancreatic and gallbladder functions. According to this aspect of the invention a composition for diagnostic use in this respect comprises an effective diagnostic amount of the secretin precursor of this invention in combination with a carrier which does not interfere with the diagnostic procedure used.
The secretin precursor of this invention is in addition therapeutically useful in that it stimulates pancreatic secretion in mammals if administered in a suitable manner. According to this aspect of the invention a composition for such use is provided comprising an effective therapeutic amount of the secretin precursor of the invention in combination with a non-toxic, pharmaceutically acceptable carrier. In this context the invention also covers a method of treating gastrointestinal disorders comprising administering a therapeuti
REFERENCES:
Hubel, Gastroenterology, vol. 62, No. 2, pp. 318-341 (1972).
Carlquist et al., Journal of Chromatography, vol. 296, pp. 143-151 (1984).
Gafvelin et al., FEBS vol. 184, No. 2, pp. 347-352 (5/1985).
Mutt et al., "On the Assay of Secretin", Ark. Kem., vol. 15, pp. 63-68 (1959).
Roth, "Fluorescence Reaction, for Amino Acids", Analytical Chemistry, vol. 43, pp. 880-882 (1971).
Koop et al., "Purification and Characterization of a Unique Isozyme of Cytochromo P-450 from Liver Microsomes of Ethanol-Treated Rabbits", J. Bio. Chem., vol. 257, pp. 8472-8480 (1982).
Heinrikson et al., "Amino Acid Analysis by Reverse-Phase High-Performance Liquid Chromatography: Precolumn Derivatization with Phenylisothiocyanate", S.C. Analytical Biochem., vol. 136, pp. 65-74 (1984).
Dimaline et al., "Multiple Immunoreactive Forms of Vasoactive Intestinal Peptide in Human Colonic Mucosa", Gastroenterology, vol. 75, pp. 387-392 (1978).
Said et al., "Isolation from Porcine-Intestinal Wall of a Vasoactive Octacosapeptide Related to Secretin and to Glucagon", Eur. J. Biochem., vol. 28, pp. 159-204 (1972).
Mutt et al., "Structure of Porcine Secretin-The Amino Acid Sequence", Eur. J. Biochem., vol. 15, pp. 513-519 (1970).
Carlquist et al., "Isolation and Amino Acid Sequence of Bovine Secretin", FEBS Letters, vol. 127, No. 1, pp. 71-74 (1981).
Carlquist Mats
Gafvelin Guro
Mutt Viktor
Chan Christina
KabiGen AB
Phillips Delbert R.
LandOfFree
Mammal intestinal hormone precursor and its use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Mammal intestinal hormone precursor and its use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Mammal intestinal hormone precursor and its use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-524414