G protein coupled receptor (GPCR) agonists and antagonists and methods of activating and inhibiting GPCR using the same

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 8 ); nonanoyl (C 9 ); capryl (C 10 ); undecanoyl (C 11 ); lauroyl (C 2 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phtanoyl ((CH 3 ) 4 ); heptadecanoyl (C 17 ); and stearoyl (C 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.