Claims
- 1. A method of identifying whether a candidate compound is a modulator of a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:36 (hRUP25); (b) SEQ. ID. NO.:137 (mRUP25); and (c) SEQ. ID. NO.:139 (rRUP25); or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence; comprising the steps of: (a′) contacting the candidate compound with the receptor; and (b′) determining whether the receptor functionality is modulated; wherein a change in receptor functionality is indicative of the candidate compound being a modulator of a nicotinic acid GPCR.
- 2. A modulator of a nicotinic acid GPCR (RUP25) identified according to the method of claim 1, provided that the modulator is not identical to a compound selected from the group consisting of:
- 3. A method of modulating the activity of a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:36 (hRUP25); (b) SEQ. ID. NO.:137 (mRUP25); and (c) SEQ. ID. NO.:139 (rRUP25); or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence; comprising the step of contacting the receptor with the modulator of claim 2.
- 4. A method of preventing or treating a disorder of lipid metabolism in an individual comprising contacting a therapeutically effective amount of the modulator of claim 2 with a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:36 (hRUP25); (b) SEQ. ID. NO.:137 (mRUP25); and (c) SEQ. ID. NO.:139 (rRUP25); or an allelic variant or biologically active fragment of said amino acid sequence.
- 5. A method of preventing or treating a metabolic-related disorder in an individual comprising contacting a therapeutically effective amount of the modulator of claim 2 with a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:36 (hRUP25); (b) SEQ. ID. NO.:137 (mRUP25); and (c) SEQ. ID. NO.:139 (rRUP25); or an allelic variant or biologically active fragment of said amino acid sequence.
- 6. A method of preparing a composition which comprises identifying a modulator of a nicotinic acid GPCR and then admixing a carrier and the modulator, wherein the modulator is identifiable by the method of claim 1 and provided that the modulator is not identical to a compound selected from the group consisting of:
- 7. A pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of the modulator of claim 2.
- 8. A method of changing lipid metabolism comprising providing or administering to an individual in need of said change said pharmaceutical or physiologically acceptable composition of claim 7.
- 9. A method of preventing or treating a metabolic-related disorder comprising providing or administering to an individual in need of said prevention or treatment said pharmaceutical or physiologically acceptable composition of claim 7.
- 10. A method of using the modulator of claim 2 for the preparation of a medicament for the treatment of a disorder in lipid metabolism in an individual.
- 11. A method of using the modulator of claim 2 for the preparation of a medicament for the treatment of a metabolic-related disorder in an individual.
- 12. A method of identifying whether a candidate compound binds to a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:36 (hRUP25); (b) SEQ. ID. NO.:137 (mRUP25); and (c) SEQ. ID. NO.:139 (rRUP25); or an allelic variant or a biologically active fragment of said amino acid sequence; comprising the steps of: (a′) contacting the receptor with a labeled reference compound known to bind to the GPCR in the presence or absence of the candidate compound; and (b′) determining whether the binding of said labeled reference compound to the receptor is inhibited in the presence of the candidate compound; wherein said inhibition is indicative of the candidate compound binding to a nicotinic acid GPCR.
- 13. A method of identifying whether a candidate compound is a modulator of an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:135 (hRUP38), or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence;
comprising the steps of: (a) contacting the candidate compound with the receptor; and (b) determining whether the receptor functionality is modulated; wherein a change in receptor functionality is indicative of the candidate compound being a modulator of an antilipolytic GPCR.
- 14. A modulator of an antilipolytic GPCR (RUP38) identified according to the method of claim 13.
- 15. A method of modulating the activity of an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.: 135 (hRUP38), or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence;
comprising the step of contacting the receptor with the modulator of claim 14.
- 16. A method of preventing or treating a disorder of lipid metabolism in an individual comprising contacting a therapeutically effective amount of the modulator of claim 14 with an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:135 (hRUP38) or an allelic variant or biologically active fragment of said amino acid sequence.
- 17. A method of preventing or treating a metabolic-related disorder in an individual comprising contacting a therapeutically effective amount of the modulator of claim 14 with an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:135 (hRUP38) or an allelic variant or biologically active fragment of said amino acid sequence.
- 18. A method of preparing a composition which comprises identifying a modulator of an antilipolytic GPCR and then admixing a carrier and the modulator, wherein the modulator is identifiable by the method of claim 13.
- 19. A pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of the modulator of claim 14.
- 20. A method of changing lipid metabolism comprising providing or administering to an individual in need of said change said pharmaceutical or physiologically acceptable composition of claim 19.
- 21. A method of preventing or treating a metabolic-related disorder comprising providing or administering to an individual in need of said prevention or treatment said pharmaceutical or physiologically acceptable composition of claim 19.
- 22. A method of using the modulator of claim 14 for the preparation of a medicament for the treatment of a disorder in lipid metabolism in an individual.
- 23. A method of using the modulator of claim 14 for the preparation of a medicament for the treatment of a metabolic-related disorder in an individual.
- 24. A method of identifying whether a candidate compound binds to an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:135 (hRUP38) or an allelic variant or a biologically active fragment of said amino acid sequence;
comprising the steps of: (a) contacting the receptor with a labeled reference compound known to bind to the GPCR in the presence or absence of the candidate compound; and (b) determining whether the binding of said labeled reference compound to the receptor is inhibited in the presence of the candidate compound; wherein said inhibition is indicative of the candidate compound binding to an antilipolytic GPCR.
- 25. A method of identifying whether a candidate compound is a modulator of an antilipolytic GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:24 (hRUP19); (b) SEQ. ID. NO.:151 (mRUP19); and (c) SEQ. ID. NO.:157 (rRUP19); or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence; comprising the steps of: (a′) contacting the candidate compound with the receptor; and (b′) determining whether the receptor functionality is modulated; wherein a change in receptor functionality is indicative of the candidate compound being a modulator of an antilipolytic GPCR.
- 26. A modulator of an antilipolytic GPCR (RUP19) identified according to the method of claim 25.
- 27. A method of modulating the activity of an antilipolytic GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:24 (hRUP19); (b) SEQ. ID. NO.:151 (mRUP19); and (c) SEQ. ID. NO.:157 (rRUP19); or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence; comprising the step of contacting the receptor with the modulator of claim 26.
- 28. A method of preventing or treating a disorder of lipid metabolism in an individual comprising contacting a therapeutically effective amount of the modulator of claim 26 with an antilipolytic GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:24 (hRUP19); (b) SEQ. ID. NO.:151 (mRUP19); and (c) SEQ. ID. NO.:157 (rRUP19); or an allelic variant or biologically active fragment of said amino acid sequence.
- 29. A method of preventing or treating a metabolic-related disorder in an individual comprising contacting a therapeutically effective amount of the modulator of claim 26 with an antilipolytic GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:24 (hRUP19); (b) SEQ. ID. NO.:151 (mRUP19); and (c) SEQ. ID. NO.:157 (rRUP19); or an allelic variant or biologically active fragment of said amino acid sequence.
- 30. A method of preparing a composition which comprises identifying a modulator of a nicotinic acid GPCR and then admixing a carrier and the modulator, wherein the modulator is identifiable by the method of claim 25.
- 31. A pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of the modulator of claim 26.
- 32. A method of changing lipid metabolism comprising providing or administering to an individual in need of said change said pharmaceutical or physiologically acceptable composition of claim 31.
- 33. A method of preventing or treating a metabolic-related disorder comprising providing or administering to an individual in need of said prevention or treatment said pharmaceutical or physiologically acceptable composition of claim 31.
- 34. A method of using the modulator of claim 26 for the preparation of a medicament for the treatment of a disorder in lipid metabolism in an individual.
- 35. A method of using the modulator of claim 26 for the preparation of a medicament for the treatment of a metabolic-related disorder in an individual.
- 36. A method of identifying whether a candidate compound binds to an antilipolytic GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
(a) SEQ. ID. NO.:24 (hRUP19); (b) SEQ. ID. NO.:151 (mRUP19); and (c) SEQ. ID. NO.:157 (rRUP19); or an allelic variant or a biologically active fragment of said amino acid sequence; comprising the steps of: (a′) contacting the receptor with a labeled reference compound known to bind to the GPCR in the presence or absence of the candidate compound; and (b′) determining whether the binding of said labeled reference compound to the receptor is inhibited in the presence of the candidate compound; wherein said inhibition is indicative of the candidate compound bind to an antilipolytic GPCR.
- 37. A method of identifying whether a candidate compound is a modulator of an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:8 (hRUP11), or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence;
comprising the steps of: (a) contacting the candidate compound with the receptor; and (b) determining whether the receptor functionality is modulated; wherein a change in receptor functionality is indicative of the candidate compound being a modulator of an antilipolytic GPCR.
- 38. A modulator of an antilipolytic GPCR (RUP11) identified according to the method of claim 37.
- 39. A method of modulating the activity of an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:8 (hRUP11), or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence;
comprising the step of contacting the receptor with the modulator of claim 38.
- 40. A method of preventing or treating a disorder of lipid metabolism in an individual comprising contacting a therapeutically effective amount of the modulator of claim 38 with an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:8 (hRUP11) or an allelic variant or biologically active fragment of said amino acid sequence.
- 41. A method of preventing or treating a metabolic-related disorder in an individual comprising contacting a therapeutically effective amount of the modulator of claim 38 with an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:8 (hRUP11) or an allelic variant or biologically active fragment of said amino acid sequence.
- 42. A method of preparing a composition which comprises identifying a modulator of an antilipolytic GPCR and then admixing a carrier and the modulator, wherein the modulator is identifiable by the method of claim 37.
- 43. A pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of the modulator of claim 38.
- 44. A method of changing lipid metabolism comprising providing or administering to an individual in need of said change said pharmaceutical or physiologically acceptable composition of claim 43.
- 45. A method of preventing or treating a metabolic-related disorder comprising providing or administering to an individual in need of said prevention or treatment said pharmaceutical or physiologically acceptable composition of claim 43.
- 46. A method of using the modulator of claim 38 for the preparation of a medicament for the treatment of a disorder in lipid metabolism in an individual.
- 47. A method of using the modulator of claim 38 for the preparation of a medicament for the treatment of a metabolic-related disorder in an individual.
- 48. A method of identifying whether a candidate compound binds to an antilipolytic GPCR, said receptor comprising the amino acid sequence of SEQ. ID. NO.:8 (hRUP11) or an allelic variant or a biologically active fragment of said amino acid sequence;
comprising the steps of:
(a) contacting the receptor with a labeled reference compound known to bind to the GPCR in the presence or absence of the candidate compound; and (b) determining whether the binding of said labeled reference compound to the receptor is inhibited in the presence of the candidate compound; wherein said inhibition is indicative of the candidate compound binding to an antilipolytic GPCR.
- 49. A method of making a mouse genetically predisposed to a metabolic-related disorder or a disorder of lipid metabolism comprising the step of knocking out the gene encoding the polypeptide of SEQ. ID. NO.:137 (mRUP25) or the polypeptide of SEQ. ID. NO.:151 (mRUP19).
- 50. A knockout mouse according to the method of claim 49.
- 51. A method of using the knockout mouse of claim 50 to identify whether a candidate compound has therapeutic efficacy for the prevention or treatment of said metabolic-related disorder or said disorder of lipid metabolism.
- 52. A method of making a rat genetically predisposed to a metabolic-related disorder or a disorder of lipid metabolism comprising the step of knocking out the gene encoding the polypeptide of SEQ. ID. NO.:139 (rRUP25) or the polypeptide of SEQ. ID. NO.:157 (rRUP19).
- 53. A knockout rat according to the method of claim 52.
- 54. A method of using the knockout rat of claim 53 to identify whether a candidate compound has therapeutic efficacy for the prevention or treatment of said metabolic-related disorder or said disorder of lipid metabolism.
- 55. A method of making a transgenic mouse comprising a human antilipolytic GPCR, comprising the step of engineering said mouse to carry as part of its own genetic material the gene encoding the polypeptide of SEQ. ID. NO.:135 (hRUP38) or the polypeptide of SEQ. ID. NO.:8 (hRUP11).
- 56. A transgenic mouse according to the method of claim 55.
- 57. A method of using the transgenic mouse of claim 56 to identify whether a modulator of said human antilipolytic GPCR has therapeutic efficacy for the prevention or treatment of a metabolic-related disorder or a disorder of lipid metabolism.
- 58. A method of making a transgenic rat comprising a human antilipolytic GPCR, comprising the step of engineering said rat to carry as part of its own genetic material the gene encoding the polypeptide of SEQ. ID. NO.:135 (hRUP38) or the polypeptide of SEQ. ID. NO.:8 (hRUP11).
- 59. A transgenic rat according to the method of claim 58.
- 60. A method of using the transgenic rat of claim 59 to identify whether a modulator of said human antilipolytic GPCR has therapeutic efficacy for the prevention or treatment of a metabolic-related disorder or a disorder of lipid metabolism.
- 61. An isolated EFA-hRUP25 polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ. ID. NO.:158; (b) a polynucleotide having the nucleotide sequence of SEQ. ID. NO.:158; (c) a polynucleotide comprising a polynucleotide encoding the polypeptide having the amino acid sequence of SEQ. ID. NO.:159 or a biologically active fragment of said polypeptide; and (d) a polynucleotide encoding the polypeptide having the amino acid sequence of SEQ. ID. NO.:159 or a biologically active fragment of said polypeptide.
- 62. An isolated EFA-hRUP25 polypeptide selected from the group consisting of:
(a) a polypeptide comprising the amino acid sequence of SEQ. ID. NO.:159, or a biologically active fragment of said polypeptide; and (b) a polypeptide having the amino acid sequence of SEQ. ID. NO.:159, or a biologically active fragment of said polypeptide.
- 63. A recombinant vector comprising the polynucleotide of claim 61.
- 64. A host cell comprising the recombinant vector of claim 63.
- 65. A method of making an EFA mutant of an endogenous GPCR polypeptide having constitutive activity, comprising the steps of:
(a) introducing 1, 2, 3, 4, or 5 substitutions, insertions, or deletions into the amino acid sequence of the endogenous GPCR polypeptide; (b) measuring the activity of the mutant GPCR of (a) in the absence of agonist and in the presence of a known agonist; (c) measuring the activity of the endogenous GPCR in the absence of agonist and in the presence of said known agonist; and (d) comparing (b) and (c); wherein a determination that the agonist screening window of (b) is at least 20% greater than that of (c) identifies the mutant resulting from (a) to be an EFA mutant of the endogenous GPCR.
Parent Case Info
[0001] This application is a continuation-in-part of U.S. Utility patent application Ser. No. 10/096,511, filed Mar. 12, 2002 and which claimed priority to U.S. application Serial No. 09/995,543, filed Nov. 27, 2001 (now abandoned); and U.S. Provisional Patent Applications: Serial No. 60/399,917, filed Jul. 29, 2002, Ser. No. 60/404,761, filed Aug. 19, 2002 and Ser. No. 60/410,747, filed Sep. 13, 2002; the disclosure of each of which is hereby incorporated by reference in its entirety.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60399917 |
Jul 2002 |
US |
|
60410747 |
Sep 2002 |
US |
|
60404761 |
Aug 2002 |
US |
Continuations (1)
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Number |
Date |
Country |
Parent |
09995543 |
Nov 2001 |
US |
Child |
10096511 |
Mar 2002 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
10096511 |
Mar 2002 |
US |
Child |
10314048 |
Dec 2002 |
US |