Claims for Patent: 6,864,229

Summary for Patent: 6,864,229

Title:	G protein coupled receptor (GPCR) agonists and antagonists and methods of activating and inhibiting GPCR using the same
Abstract:	The invention relates generally to G protein coupled receptors and in particular to agonists and antagonists of G protein receptors and methods of using the same.
Inventor(s):	Kuliopulos; Athan (Winchester, MA), Covic; Lidija (Boston, MA)
Assignee:	New England Medical Center Hospitals, Inc. (Boston, MA)
Application Number:	09/841,091
Patent Claims:	1. A chimeric polypeptide, said chimeric polypeptide comprising: a) a first domain consisting essentially of third intracellular loop (i3 loop) or a fragment thereof of a G protein coupled receptor (GPCR), and b) a second domain, attached to the first domain, wherein said second domain is a naturally or non-naturally occurring cell-penetrating, membrane-tethering hydrophobic moiety wherein said first domain does not comprise a native extracellular portion of said GPCR and wherein said chimeric polypeptide binds to its cognate GPCR. 2. The chimeric polypeptide of claim 1, wherein said hydrophobic moiety is attached at N-terminal end, the C-terminal end, or both the N-terminal and C-terminal ends of said first domain. 3. The chimeric polypeptide of claim 1, wherein said hydrophobic moiety is a lipid. 4. The chimeric polypeptide of claim 3, wherein said hydrophobic moiety is selected from the group consisting of: capryloyl (C.sub.8); nonanoyl (C.sub.9); capryl (C.sub.10); undecanoyl (C.sub.11); lauroyl (C.sub.2); tridecanoyl (C.sub.13); myristoyl (C.sub.14); pentadecanoyl (C.sub.15); palmitoyl (C.sub.16); phtanoyl ((CH.sub.3).sub.4); heptadecanoyl (C.sub.17); and stearoyl (C.sub.18), wherein said hydrophobic moiety is attached to said chimeric polypeptide with amide bonds, sulfhydryls, amines, alcohols, phenolic groups, or carbon-carbon bonds. 5. The chimeric polypeptide of claim 1, where said i3 loop or fragment thereof comprises at least 3 contiguous amino acid residues of the third intracellular loop. 6. The chimeric polypeptide of claim 1, wherein said is at least 5 i3 loop or fragment thereof comprises at least 5 contiguous amino acid residues of the third intracellular loop. 7. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises at least 7 contiguous amino acid residues of the third intracellular loop. 8. The chimeric polypeptide of claim 1, wherein said first domain comprises a protease-activated receptor (PAR) and said second domain comprises a lipid moiety. 9. The chimeric polypeptide of claim 1, wherein G-protein coupled receptor or fragment thereof, is selected from the group consisting of a luteinizing hormone receptor, a follicle stimulating hormone receptor, a thyroid stimulating hormone receptor, a calcitonin receptor, a glucagon receptor, a glucagon-like peptide 1 receptor (GLP-1), a metabotropic glutamate receptor, a parathyroid hormone receptor, a vasoactive intestinal peptide receptor, a secretin receptor, a growth hormone releasing factor (GRF) receptor, protease-activated receptors (PARs), cholecystokinin receptors, somatostatin receptors, melanocortin receptors, ADP receptors, adenosine receptors, thromboxane receptors, platelet activating factor receptor, adrenergic receptors, 5-HT receptors, CXCR4, CCR5, chemokine receptors, neuropeptide receptors, opioid receptors, parathyroid hormone (PTH) receptor, and vasoactive intestinal peptide (VIP) receptor. 10. A pharmaceutical composition comprising the chimeric polypeptide of claim 1 and a pharmaceutically acceptable carrier. 11. A kit comprising in one or more containers, the pharmaceutical composition of claim 10. 12. The chimeric polypeptide of claim 1, wherein said G-protein coupled receptor is a mammalian G-protein coupled receptor. 13. The chimeric polypeptide of claim 4, wherein said hydrophobic moiety is palmitoyl. 14. The chimeric polypeptide of claim 1, wherein said G-protein coupled receptor is a protease-activated receptor (PAR). 15. The chimeric polypeptide of claim 14, wherein the protease-activated receptor is selected from the group consisting of PAR1, PAR2, and PAR4. 16. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises a sequence selected from the group consisting of SEQ ID NO: 1-16, 19-23, and 29. 17. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment therof comprises a sequence selected from the group consisting of SEQ ID NO: 1-10, and 23. 18. The chimeric polypeptide of claim 1, wherein th said G-protein coupled receptor is selected from the group consisting of CCKA, CCKB, SSTR2, and SubP receptors. 19. The chimeric polypeptide of claim 3, wherein said hydrophobic moiety is a steroid. 20. A chimeric polypeptide, said chimeric polypeptide comprising: a) a first domain comprising an isolated i3 loop or fragment thereof of a protease-activated receptor (PAR), and b) a second domain, attached to the first domain, wherein said second domain is palmitate. 21. The chimeric polypeptide of claim 1, wherein said hydrophobic moiety is selected from the group consisting of a phospholipid, a steroid, a sphingosine, a ceramide, an octyl-glycine, a 2-cyclohexylalanine, and a benzolylphenylalanine. 22. The chimeric polypeptide of claim 1, further comprising a third domain, said third domain being a cell-penetrating, membrane tethering hydrophobic moiety attached to said first domain. 23. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:1. 24. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:2. 25. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:3. 26. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NQ:4. 27. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:5. 28. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:6. 29. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ U) NO:7. 30. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:8. 31. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:9. 32. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:10. 33. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:11. 34. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:12. 35. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:13. 36. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:14. 37. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:15. 38. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:16. 39. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:19. 40. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:20. 41. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:21. 42. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:22. 43. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:23. 44. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:28. 45. The chimeric polypeptide of claim 1, wherein said i3 loop or fragment thereof comprises the amino acid sequence of SEQ ID NO:29. 46. The chimeric polypeptide of claim 1, wherein the hydrophobic moiety is a steroid.

Details for Patent 6,864,229

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2020-04-21