Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 8 to 10 amino acid residues in defined sequence
Reexamination Certificate
2000-06-30
2002-07-16
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
8 to 10 amino acid residues in defined sequence
C435S007100, C435S007210, C435S007600, C435S198000, C530S329000, C530S330000, C514S015800
Reexamination Certificate
active
06420521
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 identified 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 aspect, the present invention provides an isolated nucleic acid molecule encoding an isolated peptide molecule selected from the group consisting of (a) residue 1 (Gly) to residue 9 (His); (b) residue 2 (Ser) to residue 9 (His); (c) residue 3 (Ser) to residue 9 (His); and (d) residue 4 (Phe) to residue 9 (His); all of SEQ NO:2. Within one embodiment, the invention provides for the isolated peptide molecule encoded by said isolated nucleic acid molecule.
Within another aspect the invention provides an isolated polypeptide molecule comprising residues X through 9 of SEQ ID NO:6, wherein X is an integer from 1 to 4, inclusive, and wherein at least Y of said residues are as in the corresponding region of SEQ ID NO:2, wherein Y is 9 minus X. Within an embodiment the invention provides a method of modulating contractility and protein secretion in stomach, duodenum or jejunum tissue comprising applying said isolated polypeptide to said tissue. Within another embodiment is provided a method of modulating pancreatic secretion of hormones and digestive enzymes in a mammal comprising administering the isolated polypeptide of claim 1 to a mammal.
Within another aspect the present invention provides an isolated polypeptide molecule consisting of residues X through Y of SEQ ID NO:6, wherein Y is 10 or 11 and X is an integer from 1 to 4, inclusive, and at least (Y minus X) minus 3 residues are as in the corresponding region of SEQ ID NO:2.
Within another aspect is provided an isolated polypeptide molecule consisting of residues X through Y of SEQ ID NO:6, wherein Y is 10 or 11 and X is an integer from 1 to 4, inclusive, and at least (Y minus X) minus 2 residues are as in the corresponding region of SEQ ID NO:2. Within an embodiment the invention provides a method of modulating contractility in duodenum or jejunum tissue comprising applying the isolated polypeptide said tissue. Within another embodiment is provided a method of modulating pancreatic secretion of hormones and digestive enzymes comprising administering the isolated polypeptide to a mammal.
Within another aspect, the invention provides an isolated polypeptide molecule consisting of residues X through Y of SEQ ID NO:6, wherein Y is 10 or 11 and X is an integer from 1 to 4, inclusive, and at least (Y minus X) minus 1 residues are as in the corresponding region of SEQ ID NO:2. Within an embodiment is provided a method of modulating contractility in duodenum or jejunum tissue comprising applying the isolated polypeptide to said tissue. Within another embodiment is provided a method of modulating pancreatic secretion of hormones and digestive enzymes comprising administering the isolated polypeptide to a mammal.
Within another aspect the invention provides an isolated polypeptide consisting of up to nine amino acids as shown in the amino acid sequence of SEQ ID NO:2. Within one embodiment the polypeptide has at its amino terminal residue 1 (Gly), residue 2 (Ser), residue 3 (Ser) or residue 4 (Phe) as shown in SEQ ID NO:2, and the polypeptide has at its carboxyl terminal residue 9 (His) as shown is SEQ ID NO:2. Within an embodiment, the polypeptide has up to one amino acid substitution. Within another embodiment, is provided a method of stimulating contractility in duodenum or jejunum tissue comprising administering the polypeptide, with or with out amino acid substitutions to the tissue. Within another embodiment is provided a method of modulating pancreatic secretion of hormones and digestive enzymes comprising administering the polypeptide, with or without substitutions, to a mammal. Within another embodiment is provided a method of stimulating growth hormone secretion comprising administering the polypeptide, with or without substitutions, to a mammal.
Within another aspect the invention provides an isolated polypeptide wherein the polypeptide has at its amino terminal residue 2 (Ser), residue 3 (Ser) or residue 4 (Phe) as shown in SEQ ID NO:2, and the polypeptide has at its carboxyl terminal residue 10 (Gln) as shown is SEQ ID NO:2. Within an embodiment, the polypeptide has up to three amino acid substitutions. Within another embodiment, is provided a method of stimulating contractility in duodenum or jejunum tissue comprising administering the polypeptide, with or with out amino acid substitutions to the tissue. Within another embodiment is provided a method of modulating panc
Bishop Paul D.
Deisher Theresa A.
Jaspers Stephen R.
Sheppard Paul O.
Adams Robyn
Liu Samuel Wei
Low Christopher S. F.
Zymogenetics Inc.
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