US 2009/0253153 A1 · METHODS OF USING A G PROTEIN-COUPLED RECEPTOR TO IDENTIFY PEPTIDE YY (PYY) SECRETAGOGUES AND COMPOUNDS USEFUL IN THE TREATMENT OF CONDITIONS MODULATED BY PYY

A method for identifying a peptide YY (PYY) secretagogue, comprising:

(a) contacting a test compound with a host cell or with membrane of a host cell comprising a G protein-coupled receptor wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) determining the ability of the test compound to stimulate functionality of the G protein-coupled receptor, wherein the ability of the test compound to stimulate functionality of the G protein-coupled receptor is indicative of the test compound being a PYY secretagogue;
(c) contacting a compound which stimulates functionality of the G protein-coupled receptor in step (b) with a vertebrate enteroendocrine cell or a cell capable of secreting PYY in vitro;
and
(d) determining whether the compound stimulates PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY,
wherein the ability of the test compound to stimulate PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY is further indicative of the test compound being a PYY secretagogue.

15 more elements

A method for identifying a peptide YY (PYY) secretagogue, comprising:

(a) contacting a test compound with a host cell or with membrane of a host cell comprising a G protein-coupled receptor wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) determining the ability of the test compound to stimulate functionality of the G protein-coupled receptor, wherein the ability of the test compound to stimulate functionality of the G protein-coupled receptor is indicative of the test compound being a PYY secretagogue;
(c) determining whether the compound increases a PYY level in a sample, the sample having been obtained from a vertebrate previously administered with a compound which stimulates functionality of the G protein-coupled receptor in step (b),
wherein the ability of the test compound to increase a PYY level in the vertebrate is further indicative of the test compound being a PYY secretagogue.

13 more elements

A method for identifying a peptide YY (PYY) secretagogue, comprising:

(a) contacting a test compound with a host cell or with membrane of a host cell comprising a G protein-coupled receptor wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) determining the ability of the test compound to stimulate functionality of the G protein-coupled receptor, wherein the ability of the test compound to stimulate functionality of the G protein-coupled receptor is indicative of the test compound being a PYY secretagogue;
(c) administering a compound which stimulates functionality of the G protein-coupled receptor in step (b) to a vertebrate;
and
(d) determining whether the compound increases a PYY level in the vertebrate,
wherein the ability of the test compound to increase a PYY level in the vertebrate is further indicative of the test compound being a PYY secretagogue.

15 more elements

A method for identifying a PYY secretagogue, comprising:

(a) contacting a G protein-coupled receptor with a ligand for the G protein-coupled receptor in the presence of a test compound, wherein a ligand for the G protein-coupled receptor is a ligand for GPR119 and wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) detecting the complex between the ligand and the G protein-coupled receptor;
and
(c) determining whether less of the complex is formed in the presence of the test compound than in the absence of the test compound, wherein a determination that less of the complex is formed in the presence of the test compound than in the absence of the test compound is indicative of the test compound being a PYY secretagogue;
(d) contacting a compound in the presence of which less of the complex is formed in step (c) in vitro with a vertebrate enteroendocrine cell or a cell capable of secreting PYY;
and
(e) determining whether the compound stimulates PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY,
wherein the ability of the test compound to stimulate PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY is further indicative of the test compound being a PYY secretagogue.

17 more elements

A method for identifying a PYY secretagogue, comprising:

(a) contacting a G protein-coupled receptor with a ligand for the G protein-coupled receptor in the presence of a test compound, wherein a ligand for the G protein-coupled receptor is a ligand for GPR119 and wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) detecting the complex between the ligand and the G protein-coupled receptor;
and
(c) determining whether less of the complex is formed in the presence of the test compound than in the absence of the test compound, wherein a determination that less of the complex is formed in the presence of the test compound than in the absence of the test compound is indicative of the test compound being a PYY secretagogue;
(d) determining whether the compound increases a PYY level in a sample obtained from a vertebrate, the vertebrate having been administered with a compound in the presence of which less of the complex is formed in step (c),
wherein the ability of the test compound to increase a PYY level in the vertebrate is further indicative of the test compound being a PYY secretagogue.

15 more elements

A method for identifying a PYY secretagogue, comprising:

(a) contacting a G protein-coupled receptor with a ligand for the G protein-coupled receptor in the presence or absence of a test compound, wherein a ligand for the G protein-coupled receptor is a ligand for GPR119 and wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) detecting the complex between the ligand and the G protein-coupled receptor;
and
(c) determining whether less of the complex is formed in the presence of the test compound than in the absence of the test compound, wherein a determination that less of the complex is formed in the presence of the test compound than in the absence of the test compound is indicative of the test compound being a PYY secretagogue;
(d) administering a compound in the presence of which less of the complex is formed in step (c) to a vertebrate;
and
(e) determining whether the compound increases a PYY level in the vertebrate,
wherein the ability of the test compound to increase a PYY level in the vertebrate is further indicative of the test compound being a PYY secretagogue.

17 more elements

A method for identifying compounds useful for treatment or prevention of a condition modulated by peptide YY (PYY), the method comprising:

(a) contacting a test compound with a host cell or with membrane of a host cell comprising a G protein-coupled receptor wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) determining the ability of the test compound to stimulate functionality of the G protein-coupled receptor, wherein the ability of the test compound to stimulate functionality of the G protein-coupled receptor is indicative of the test compound being a compound useful for treatment or prevention of a condition modulated by PYY;
(c) contacting a compound which stimulates functionality of the G protein-coupled receptor in step (b) with a vertebrate enteroendocrine cell or a cell capable of secreting PYY in vitro;
and
(d) determining whether the compound stimulates PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY,
wherein the ability of the test compound to stimulate PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY is further indicative of the test compound being a compound useful for treatment or prevention of a condition modulated by PYY.

15 more elements

A method for identifying compounds useful for treatment or prevention of a condition modulated by peptide YY (PYY), the method comprising:

(a) contacting a G protein-coupled receptor with a ligand for the G protein-coupled receptor in the presence or absence of a test compound, wherein a ligand for the G protein-coupled receptor is a ligand for GPR119 and wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) detecting the complex between the ligand and the G protein-coupled receptor;
and
(c) determining whether less of the complex is formed in the presence of the test compound than in the absence of the test compound, wherein a determination that less of the complex is formed in the presence of the test compound than in the absence of the test compound is indicative of the test compound being a compound useful for treatment or prevention of a condition modulated by PYY;
(d) contacting a compound in the presence of which less of the complex is formed in step (c) with a vertebrate enteroendocrine cell or a cell capable of secreting PYY in vitro;
and
(e) determining whether the compound stimulates PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY,
wherein the ability of the test compound to stimulate PYY secretion from the vertebrate enteroendocrine cell or the cell capable of secreting PYY is further indicative of the test compound being a compound useful for treatment or prevention of a condition modulated by PYY.

17 more elements

A method for identifying compounds useful for a modulation of a PYY-related activity in an individual, the method comprising:

(a) contacting a test compound with a host cell or with membrane of a host cell comprising a G protein-coupled receptor wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) determining the ability of the test compound to stimulate functionality of the G protein-coupled receptor, wherein the ability of the test compound to stimulate functionality of the G protein-coupled receptor is indicative of the test compound being a compound useful for a modulation of a PYY-related activity in an individual;
(c) determining whether the compound increases a PYY level in a sample, the sample having been obtained from a vertebrate previously administered with a compound which stimulates functionality of the G protein-coupled receptor in step (b),
wherein the ability of the test compound to increase a PYY level in the vertebrate is further indicative of the test compound being a compound useful for a modulation of a PYY-related activity in an individual.

13 more elements

A method for identifying compounds useful for modulation of a PYY-related activity in an individual, the method comprising:

(a) contacting a G protein-coupled receptor with a ligand for the G protein-coupled receptor in the presence or absence of a test compound, wherein a ligand for the G protein-coupled receptor is a ligand for GPR119 and wherein the G protein-coupled receptor comprises an amino acid sequence selected from the group consisting of:
(i) amino acids 1-335 of SEQ ID NO:2;
(ii) amino acids 2-335 of SEQ ID NO:2;
(iii) an amino acid sequence comprising the amino acid sequence of a polypeptide derived from (i) by substitution, deletion or addition of one or several amino acids in the amino acid sequence defined in (i);
(iv) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide capable of hybridizing under stringent conditions to the complement of the nucleotide sequence set forth in SEQ ID NO:1;
(v) the amino acid sequence of a variant of SEQ ID NO:2 selected from the group consisting of:
(a′) the amino acid sequence of a G protein-coupled receptor having at least about 80% identity to the amino acid sequence set forth in SEQ ID NO:2;
and
(b′) the amino acid sequence of a G protein-coupled receptor comprising at least 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:2;
(vi) the amino acid sequence of a constitutively active version of a G protein-coupled receptor having the amino acid sequence set forth in SEQ ID NO:2;
and
(vii) a biologically active fragment of any one of (i) to (vi);
and
(b) detecting the complex between the ligand and the G protein-coupled receptor;
and
(c) determining whether less of the complex is formed in the presence of the test compound than in the absence of the test compound, wherein a determination that less of the complex is formed in the presence of the test compound than in the absence of the test compound is indicative of the test compound being a compound useful for a modulation of a PYY-related activity in an individual.

13 more elements

Methods of using a g protein-coupled receptor to identify peptide yy (pyy) secretagogues and compounds useful in the treatment of conditions modulated by pyy

Life of this patent

Methods of using a g protein-coupled receptor to identify peptide yy (pyy) secretagogues and compounds useful in the treatment of conditions modulated by pyy

Life of this patent

Abstract

Claims109