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
Reexamination Certificate
1999-09-23
2003-09-30
Romeo, David S. (Department: 1647)
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
C530S327000, C530S328000, C530S309000
Reexamination Certificate
active
06627729
ABSTRACT:
BACKGROUND OF THE INVENTION
Many of the regulatory peptides that are important in maintaining nutritional homeostasis are found in the gastrointestinal environment. These peptides may be synthesized in the digestive system and act locally, but can also be identified in the brain as well. In addition, the reverse is also found, i.e., peptides are synthesized in the brain, but found to regulate cells in the gastrointestinal tract. This phenomena has been called the “brain-gut axis” and is important for signaling satiety, regulating body temperature and other physiological processes that require feedback between the brain and gut.
The gut peptide hormones include gastrin, cholecystokinin (CCK), secretin, gastric inhibitory peptide (GIP), vasoactive intestinal polypeptide (VIP), motilin, somatostatin, pancreatic peptide (PP), substance P and neuropeptide Y (NPY), and use several different mechanisms of action. For example, gastrin, motilin and CCK function as endocrine- and neurocrine-type hormones. Others, such as gastrin and GIP, are thought to act exclusively in an endocrine fashion. Other modes of action include a combination of endocrine, neurocrine and paracrine action (somatostatin); exclusively neurocrine action (NPY); and a combination of neurocrine and paracrine actions (VIP and Substance P). Most of the gut hormone actions are mediated by membrane-bound receptors and activate second messenger systems. For a review of gut peptides see, Mulvihill et al., in
Basic and Clinical Endocrinology,
pp.551-570, 4th edition Greenspan F. S. and Baxter, J. D. editors., Appleton & Lange: Norwalk, Conn., 1994.
Many of these gut peptides are synthesized as inactive precursor molecules that require multiple peptide cleavages to be activated. The family known as the “glucagon-secretin” family, which includes VIP, gastrin, secretin, motilin, glucagon and galanin, exemplifies peptides regulated by multiple cleavages and post-translational modifications.
Motilin is a 22 amino acid peptide found in gut tissue of mammalian species (Domschke, W.,
Digestive Diseases
22(5):454-461, 1977). The DNA and amino acid sequences for porcine prepromotilin have been identified (U.S. Pat. No. 5,006,469). Motilin has been characterized as a factor capable of increasing gastric motility, affecting the secretory function of the stomach by stimulating pepsin secretion (Brown et al.,
Canadian J. of Physiol. Pharmacol.
49:399-405, 1971), and recent evidence suggests a role in myoelectric regulation of stomach and small intestine. Cyclic increases of motilin have been correlated with phase III of the interdigestive myoelectric complex and the hunger contraction of the duodenum (Chey et al., in
Gut Hormones,
(eds.) Bloom, S. R., pp. 355-358, Edinburgh, Churchill Livingstone, 1978; Lee et al,
Am. J. Digestive Diseases,
23:789-795, 1978; and Itoh et al.,
Am. J. Digestive Diseases,
23:929-935, 1978). Motilin and analogues of motilin have been demonstrated to produce contraction of gastrointestinal smooth muscle, but not other types of smooth muscle cells (Strunz et al.,
Gastroenterology
68:1485-1491, 1975).
The present invention is directed to a novel peptide fragment, and the DNA segment encoding it, of a previously described secreted protein, zsig33 (Sheppard, P. O., WO98/42840:1998). The present invention is also directed to a limited number of variants of said peptide fragment. The discovery of this novel peptide fragment is important for further elucidation of the how the body maintains its nutritional homeostasis and development of therapeutics to intervene in those processes, as well as other uses that will be apparent from the teachings herein.
SUMMARY OF THE INVENTION
Within one apsect the present invention provides an isolated polynucleotide molecule encoding an isolated peptide molecule as shown in SEQ ID NO:12, said peptide molecule consisting of residues X through Y, wherein X is an integer from 1 to 4, inclusive, and wherein Y is 14 or 18, and wherein at least (Y minus X) minus 2 residues are as in the corresponding region of SEQ ID NO:11. Within one embodiment, the isolated peptide molecule has at least (Y minus X) minus 1 residues that are as in the corresponding region of SEQ ID NO:11. Within another embodiment, the isolated polypeptide molecule has at least (Y minus X) residues that are as in the corresponding region of SEQ ID NO:11. Within another embodiment, these isolated peptide molecule are provided. Methods for modulating contractility in duodenum or jejunum tissue and for modulating pancreatic secretion of hormones and digestive enzymes comprising administering these peptides are also provided.
Within another aspect, the present invention provides an isolated polynucleotide molecule encoding an isolated peptide molecule as shown in SEQ ID NO:12, said peptide molecule consisting of residues X through 11, wherein X is 1 or 2, and wherein at least (11 minus X) minus 2 residues are as in the corresponding region of SEQ ID NO:11. Within an embodiment, said peptide molecule has at least (11 minus X) minus 1 residues that are as in the corresponding region of SEQ ID NO:11. Within another embodiment, said polypeptide molecule has at least 11 minus X residues that are as in the corresponding region of SEQ ID NO:11. Within another embodiment, these isolated peptide molecules are provided. Methods of modulating contractility in duodenum or jejunum tissue and pancreatic secretion of hormones and digestive enzymes comprising administering said isolated polypeptide are also provided.
Within another aspect, the invention provides an isolated polynucleotide molecule encoding an isolated peptide molecule as shown in SEQ ID NO:12, said peptide molecule consisting of residues 1 through 10, and wherein at least seven residues are as in the corresponding region of SEQ ID NO:11. Within an embodiment, said isolated peptide has at least eight residues that are as in the corresponding region of SEQ ID NO:11 above. Within another embodiment, said isolated peptide has at least nine residues that are as in the corresponding region of SEQ ID NO:11. Within another embodiment, these isolated peptide molecules are provided. Methods for modulating contractility in duodenum or jejunum tissue, and for modulating pancreatic secretion of hormones and digestive enzymes comprising administering said isolated polypeptide to a mammal are also provided.
Within another aspect is provided an isolated polynucleotide molecule encoding an isolated peptide, wherein the peptide is selected from the group consisting of: a) residues 2 to 18 of SEQ ID NO:11; b) residues 2 to 14 of SEQ ID NO:11; c) residues 3 to 18 of SEQ ID NO:11; d) residues 3 to 14 of SEQ ID NO:11; e) residues 4 to 18 of SEQ ID NO:11; f) residues 4 to 14 of SEQ ID NO:11; g) residues 1 to 11 of SEQ ID NO:11; h) residues 1 to 10 of SEQ ID NO:11; and i) residues 2 to 11 of SEQ ID NO:11. Within an embodiment, the invention provides the isolated peptide molecule described herein. Within another aspect is provided a method of modulating contractility in duodenum or jejunum tissue comprising applying the isolated peptide to said tissue. Within another embodiment the invention provides a method of modulating pancreatic secretion of hormones and digestive enzymes comprising administering the isolated peptide to a mammal.
DETAILED DESCRIPTION OF THE INVENTION
Prior to describing the present invention in detail, it may be helpful to define certain terms used herein:
The term “ortholog” denotes a polypeptide or protein obtained from one species that is the functional counterpart of a polypeptide or protein from a different species. Sequence differences among orthologs are the result of speciation.
“Paralogs” are distinct but structurally related proteins made by an organism. Paralogs are believed to arise through gene duplication. For example, &agr;-globin, &bgr;-globin, and myoglobin are paralogs of each other.
The term “allelic variant” denotes any of two or more alternative forms of a gene occupying the same chromosomal locus. Allelic variation arises naturally through
Bishop Paul D.
Deisher Theresa A.
Jaspers Stephen R.
Sheppard Paul O.
Adams Robyn
Romeo David S.
ZymoGenetics Inc.
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