Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
AssigneeAmylin Pharmaceuticals, Inc.
InventorsOdile Levy, Carolyn Jodka, Soumitra Ghosh, David Parkes, Richard Pittner, Lawrence D'Souza, John Ahn, Kathryn Prickett, Jonathan Roth, Sean Adams
Life of this patent
Estimating the term…
Abstract
The present invention provides novel Pancreatic Polypeptide Family (“PPF”) polypeptides and methods for their use.
Claims53
A PPF polypeptide comprising an amino acid sequence of Formula (VI):
- Xaa1 Xaa2 Xaa3 Xaa4 Pro Glu Xaa7 Pro Xaa9 Glu Asp
- Xaa12 Xaa13 Xaa14 Glu Xaa16 Xaa17 Xaa18 Xaa19 Tyr
- Xaa21 Xaa22 Xaa23 Leu Xaa25 Xaa26 Tyr Xaa28 Asn
- Xaa30 Xaa31 Thr Arg Gln Xaa35 Xaa36
- wherein:
- Xaa1 is Tyr or absent;
- Xaa2 is Ile, Pro, or absent;
- Xaa3 is Ile, BH-modified Lys, Lys, Val, or Pro;
- Xaa4 is Lys, BH-modified Lys, Ala, Ser, or Arg;
- Xaa7 is Ala, Gly, or His;
- Xaa9 is Gly or Ala;
- Xaa12 is Ala or Pro;
- Xaa13 is Ser or Pro;
- Xaa14 is Pro, Ala, or Ser;
- Xaa16 is Glu or Asp;
- Xaa17 is Leu or Ile;
- Xaa18 is Asn or Ala;
- Xaa19 is Arg, Lys, BH-modified Lys, Gln, or N(Me)Ala;
- Xaa21 is Tyr, Ala, Phe, Lys or BH-modified Lys;
- Xaa22 is Ala or Ser;
- Xaa23 is Ser, Ala, or Asp;
- Xaa25 is Arg, Lys or BH-modified Lys;
- Xaa26 is His, Ala, or Arg;
- Xaa28 is Leu or Ile;
- Xaa30 is Leu or Met;
- Xaa31 is Val, Ile, or Leu;
- Xaa35 is Lys, BH-modified Lys, or Arg;
- and
- Xaa36 is Tyr, Trp, or Phe;
- with the proviso that said PPF polypeptide is not a native PPF polypeptide, PYY(2-36), Val3hPYY(3-36), Lys25hPYY(3-36), Lys25Ile28hPYY(3-36), Lys25Ile31hPYY(3-36), Lys25 Leu31hPYY(3-36), Lys25Phe36hPYY(3-36), Ile28hPYY(3-36), Ile31hPYY(3-36), Leu31hPYY(3-36), Phe36hPYY(3-36), Leu31 Phe36hPYY(3-36), or Pro13Ala14hPYY.
A PPF polypeptide comprising an amino acid sequence of Formula (VII):
- Xaa1 Xaa2 Pro Xaa4 Pro Xaa6 His Pro Xaa9 Xaa10
- Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Ala
- Xaa19 Tyr Xaa21 Xaa22 Xaa23 Leu Xaa25 Xaa26 Xaa27
- Xaa28 Xaa29 Xaa30 Xaa31 Thr Arg Gln Arg Tyr
- wherein:
- Xaa1 is Tyr or absent;
- Xaa2 is Ile, Pro, or absent;
- Xaa4 is Lys, BH-modified Lys, Ala, Ser, or Arg;
- Xaa6 is Glu, Gln, Ala, Asn, Asp, or Val;
- Xaa9 is Gly or Ala;
- Xaa10 is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib;
- Xaa11 is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib;
- Xaa12 is Ala or Pro;
- Xaa13 is Ser or Pro;
- Xaa14 is Pro, Ala, or Ser;
- Xaa15 is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib;
- Xaa16 is Glu or Asp;
- Xaa17 is Leu or Ile;
- Xaa19 is Arg, Lys, BH-modified Lys, Gln, or N(Me)Ala;
- Xaa21 is Tyr, Ala, Phe, Lys, or BH-modified Lys;
- Xaa22 is Ala or Ser;
- Xaa23 is Ser, Ala, or Asp;
- Xaa25 is Arg, Lys or BH-modified Lys;
- Xaa26 is His, Ala, or Arg;
- Xaa27 is Tyr, or Phe;
- Xaa28 is Leu or Ile;
- Xaa29 is Asn, or Gln;
- Xaa30 is Leu or Met;
- and
- Xaa31 is Val, Ile, or Leu.
A PPF polypeptide comprising:
- an N-terminal fragment consisting essentially of the first 17 amino acid residues of native human PYY (SEQ ID NO:
- 2);
- and
- a C-terminal fragment consisting essentially of amino acid residues 18-36 of native human NPY (SEQ ID NO:
- 4), wherein the N-terminal and C-terminal fragments are covalently linked, wherein no more than two amino acid residues at the N-terminus of the PYY fragment may be deleted or absent, and wherein no more than nine amino acid substitutions may be made in each of the N-terminal and C-terminal fragments.
A PPF polypeptide from about 34 to about 36 amino acids in length, comprising:
- an N-terminal fragment consisting essentially of 17 amino acids exhibiting at least 50% sequence identity to the first 17 amino acids of a native PYY;
- and
- a C-terminal fragment consisting essentially of 19 amino acids exhibiting at least 50% sequence identity to amino acids 18-36 of a native NPY, wherein the N-terminal and C-terminal fragments are covalently linked, and wherein one or two amino acid residues at the N-terminus of the PYY fragment may be deleted or absent.
A PPF polypeptide comprising SEQ ID NO:
- 266.
A PPF polypeptide comprising SEQ ID NO:
- 267.
A PPF polypeptide comprising SEQ ID NO:
- 274.
A PPF polypeptide comprising SEQ ID NO:
- 282.
A PPF polypeptide comprising SEQ ID NO:
- 320.
A PPF polypeptide comprising SEQ ID NO:
- 436.
A PPF polypeptide comprising SEQ ID NO:
- 437.
A PPF polypeptide comprising SEQ ID NO:
- 438.
A PPF polypeptide comprising SEQ ID NO:
- 439.
A PPF polypeptide comprising SEQ ID NO:
- 440.
A PPF polypeptide comprising SEQ ID NO:
- 441.
A PPF polypeptide comprising SEQ ID NO:
- 442.
A PPF polypeptide comprising SEQ ID NO:
- 474.
A method for altering body composition of a subject, comprising administering to the subject a PPF polypeptide, wherein the PPF polypeptide alters the fat to lean ratio, thereby altering body composition.
A method for preferentially lowering plasma triglyceride levels in a subject, comprising administering to the subject an amount of a PPF polypeptide effective to lower plasma triglyceride levels, wherein cholesterol levels are lowered to a lesser extent.
A method for reducing body fat or body fat gain in a subject while maintaining or increasing lean body mass, comprising administering to the subject an amount of a PPF polypeptide effective to reduce body fat or body fat gain while maintaining or increasing lean body mass.
A method of reducing central body fat in a subject, comprising administering to the subject an amount of a PPF polypeptide effective to reduce central body fat and preserve or increase lean body mass.
A method of increasing fatty acid β-oxidation while preserving or increasing lean body mass in a subject comprising administering to the subject an amount of a PPF polypeptide effective to increase fatty acid β-oxidation while preserving or increasing lean body mass.
A method of treating nonalcoholic steatohepatitis or lipodystrophy in a subject comprising administering to the subject an amount of a PPF polypeptide effective to treat nonalcoholic steatohepatitis or lipodystrophy.
Dependencies are inferred from the claim text.