Claims for Patent: 8,324,172

Summary for Patent: 8,324,172

Title:	G protein coupled receptor agonists and antagonists and methods of activating and inhibiting G protein coupled receptors 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 (Somerville, MA)
Assignee:	Tufts Medical Center, Inc. (Boston, MA)
Application Number:	11/606,368
Patent Claims:	1. A chimeric polypeptide comprising: a) a first domain comprising a first intracellular loop (i1 loop) or a fragment thereof of a G protein coupled receptor (GPCR), wherein said GPCR is a Class A or Class B GPCR, and b) a second domain, attached to the first domain, wherein said second domain comprises a cell-penetrating, membrane-tethering hydrophobic moiety comprising a lipid, a cholesterol, or a steroid; wherein said chimeric polypeptide is an agonist or antagonist of the GPCR, wherein said first domain does not comprise a native extracellular portion of said GPCR and wherein said i1 loop fragment comprises at least 5 contiguous amino acid residues of the first intracellular loop. 2. The chimeric polypeptide of claim 1, wherein said second domain is attached at the N-terminal end of said first domain. 3. The chimeric polypeptide of claim 1, wherein said second domain comprises a hydrophobic moiety that is selected from the group consisting of a: capryloyl (C.sub.8); nonanoyl(C.sub.9); capryl(C.sub.10); undecanoyl(C.sub.11); lauroyl(C.sub.12); tridecanoyl(C.sub.13); myristoyl(C.sub.14); pentadecanoyl(C.sub.15); palmitoyl (C.sub.16); phytanoyl ((CH.sub.3).sub.4); heptadecanoyl(C.sub.17); stearoyl(C.sub.18); nonadecanoyl(C.sub.19); arachidoyl(C.sub.20); heniecosanoyl(C.sub.21); behenoyl(C.sub.22); trucisanoyl(C.sub.23); and lignoceroyl(C.sub.24) moiety. 4. The chimeric polypeptide of claim 3, wherein said second domain comprises a palmitoyl moiety. 5. The chimeric polypeptide of claim 1, wherein said i1 loop fragment comprises at least 7 contiguous amino acid residues of the first intracellular loop. 6. The chimeric polypeptide of claim 1, wherein said GPCR is a protease-activated receptor (PAR). 7. The chimeric polypeptide of claim 6, wherein the protease-activated receptor is selected from the group consisting of PAR1, PAR2, and PAR4. 8. The chimeric polypeptide of claim 1, wherein the G-protein coupled receptor 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 secretin receptor, a growth hormone releasing factor (GRF) receptor, a protease-activated receptor (PAR), a cholecystokinin receptor, a somatostatin receptor, a melanocortin receptor, an Adenosine Diphosphate (ADP) receptor, an adenosine receptor, a thromboxane receptor, a platelet activating factor receptor, an adrenergic receptor, a 5-HT receptor, CXCR4, CCR5, a chemokine receptor, a neuropeptide receptor, an opioid receptor, a parathyroid hormone (PTH) receptor, and a vasoactive intestinal peptide (VIP) receptor. 9. A pharmaceutical composition comprising the chimeric polypeptide of claim 1 and a pharmaceutically acceptable carrier. 10. The chimeric polypeptide of claim 1, wherein the said G-protein coupled receptor is selected from the group consisting of Cholecystokinin A (CCKA) receptor, Cholecystokinin B (CCKB) receptor, Somatostatin Receptor Subtype 2 (SSTR2), and Substance P (SubP) receptor. 11. The chimeric polypeptide of claim 1, wherein said second domain comprises a steroid. 12. The chimeric polypeptide of claim 1, wherein said second domain comprises a lipid moiety. 13. The chimeric polypeptide of claim 1, wherein said GPCR is a chemokine receptor. 14. The chimeric polypeptide of claim 13, wherein said chemokine receptor is CXCR4 or CCR5. 15. The chimeric polypeptide of claim 1, wherein said GPCR is a Class A GPCR. 16. The chimeric polypeptide of claim 1, wherein said GPCR is a Class B GPCR. 17. The chimeric polypeptide of claim 1, wherein the second domain is attached at the C-terminal end of the first domain. 18. The chimeric polypeptide of claim 1, wherein the second domain comprises a myristoyl(C.sub.14) or pentadecanoyl(C.sub.15) moiety. 19. The chimeric polypeptide of claim 1, wherein the second domain comprises a cholesterol. 20. A kit comprising (1) a pharmaceutical composition comprising a chimeric polypeptide and a pharmaceutically acceptable carrier, (2) a container, pack, or dispenser, and (3) instructions for administration, wherein said chimeric polypeptide comprises: a) a first domain comprising a first intracellular loop (i1 loop) or a fragment thereof of a G protein coupled receptor (GPCR), wherein said GPCR is a Class A or Class B GPCR, and b) a second domain, attached to the first domain, wherein said second domain comprises a cell-penetrating, membrane-tethering hydrophobic moiety comprising a lipid, a cholesterol, a phospholipid, a steroid, a sphingosine, a ceramide, an octyl-glycine, a 2-cyclohexylalanine, or a benzolylphenylalanine; wherein said chimeric polypeptide is an agonist or antagonist of the GPCR, wherein said first domain does not comprise a native extracellular portion of said GPCR and wherein said i1 loop fragment comprises at least 5 contiguous amino acid residues of the first intracellular loop. 21. The kit of claim 20, wherein said second domain of the chimeric polypeptide comprises a lipid moiety. 22. The kit of claim 20, wherein the second domain comprises a palmitoyl(C.sub.16), myristoyl(C.sub.14), or pentadecanoyl(C.sub.15) moiety. 23. The kit of claim 20, wherein the second domain comprises a cholesterol. 24. A chimeric polypeptide comprising: a) a first domain comprising an isolated i1loop or fragment thereof of a protease-activated receptor (PAR), and b) a second domain, attached to the first domain, wherein said second domain comprises a palmitoyl; wherein said chimeric polypeptide is an agonist or antagonist of said PAR, wherein said first domain does not comprise a native extracellular portion of said PAR and wherein said i1 loop fragment comprises at least 5 contiguous amino acid residues of the first intracellular loop. 25. A chimeric polypeptide comprising: a) a first domain comprising a first intracellular loop (i1 loop) or a fragment thereof of a G protein coupled receptor (GPCR), wherein said GPCR is a Class A or Class B GPCR, and b) a second domain, attached to the first domain, wherein said second domain comprises a cell-penetrating, membrane-tethering hydrophobic moiety selected from the group consisting of a phospholipid, a sphingosine, a ceramide, an octyl-glycine, a 2-cyclohexylalanine, and a benzolylphenylalanine, wherein said chimeric polypeptide is an agonist or antagonist of the GPCR, wherein said first domain does not comprise a native extracellular portion of said GPCR and wherein said i1 loop fragment comprises at least 5 contiguous amino acid residues of the first intracellular loop.

Details for Patent 8,324,172

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