Modified GIP Peptide Analogues
AssigneeAntag Therapeutics ApS
InventorsAlexander Hovard SPARRE-ULRICH, Bjørn Behrens SIVERTSEN, Ditte RIBER, Mette Marie ROSENKILDE
Life of this patent
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Abstract
Disclosed are glucose-dependent insulinotropic peptide (GIP)-derived peptide analogues which are antagonists of the GIP receptor. These GIP peptide analogues are modified by comprising one or more individual amino acid substitutions and are fatty acid conjugated with/without a linker, so to have improved antagonistic activity and improved pharmacokinetic profile.
Claims56
A glucose-dependent insulinotropic peptide (GIP) analogue consisting of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]):
- 3 4 5 6 7 8 9 10 11 12 13 14
- X1 - G - T - F - I - S - D - Y - S - I - A - M -
- 15 16 17
- D - R - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - D - F - V - N - W - L - L - A - Q - X3
- wherein said amino acid X1 is selected from a group consisting of P, G, A, S and pyroE (pyroglutamic acid),
- wherein said amino acid X2 is selected from a group consisting of K and Orn,
- wherein said amino acid X3 is selected from a group consisting of R and E,
- or a functional variant thereof, wherein said variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]),
- wherein said peptide is modified by attaching at least one fatty acid molecule at the amino acid at position 18 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]), or a functional variant thereof.
The GIP peptide analogue of any one of the preceding claims, wherein the amino acid at position 18 is a lysine, and wherein at least one fatty acid molecule is attached to the side chain amino group of the lysine at position 18 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]) or a functional variant thereof.
The GIP peptide analogue of any one of the preceding claims, wherein said functional variant has 1 individual amino acid substitution at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]), such as 2 individual amino acid substitutions, such as 3 individual amino acid substitutions, for example 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]).
The GIP peptide analogue of any one of the preceding claims, wherein said fatty acid molecule is attached to the epsilon-amino group of the K at position 18 of SEQ ID NO:
- (hGIP3-30, [E3X1, K16R, H18X2, K30X3]), or a functional variant thereof.
A glucose-dependent insulinotropic peptide (GIP) analogue selected from the group consisting of:
- a peptide consisting of SEQ ID NO:
- (hGIP3-30 [K16R, H18X2, K30X3]):
- 3 4 5 6 7 8 9 10 11 12 13 14
- X1 - G - T - F - I - S - D - Y - S - I - A - M -
- 15 16 17
- D - R - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - D - F - V - N - W - L - L - A - Q - X3
- and
- a peptide consisting of SEQ ID NO:
- (hGIP5-30 [K16R, H18X2, K30X3]):
- 5 6 7 8 9 10 11 12 13 14 15 16 17
- T - F - I - S - D - Y - S - I - A - M - D - R - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - D - F - V - N - W - L - L - A - Q - X3
- wherein said amino acid X1 may be selected from a group consisting of E, P, G, A, S and pyroE,
- wherein said amino acid X2 may be selected from a group consisting of K and Orn,
- wherein said amino acid X3 may be selected from a group consisting of R and E,
- or a functional variant thereof, wherein said functional variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of any one of SEQ ID NO:
- (hGIP5-30, [K16R, H18X2, K30X3]) and SEQ ID NO:
- (hGIP3-30, [K16R, H18X2, K30X3]),
- wherein said peptide is modified by attaching at least one fatty acid molecule at the amino acid at position 18 via a linker.
The GIP peptide analogue of any one of the preceding claims, wherein said functional variant has 1 individual amino acid substitution at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of SEQ ID NO:
- (hGIP5-30, [K16R, H18X2, K30X3]) and SEQ ID NO:
- (hGIP3-30, [K16R, H18X2, K30X3]), such as 2 individual amino acid substitutions, such as 3 individual amino acid substitutions, for example 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of any one of SEQ ID NO:
- (hGIP5-30, [K16R, H18X2, K30X3]) and SEQ ID NO:
- (hGIP3-30, [K16R, H18X2, K30X3]).
The GIP peptide analogue of any one of the preceding claims, wherein the amino acid in position 18 is a lysine, and wherein at least one fatty acid molecule is attached to the side chain amino group of the lysine at position 18 of any one of SEQ ID NO:
- (hGIP5-30, [K16R, H18X2, K30X3]) and SEQ ID NO:
- (hGIP3-30, [K16R, H18X2, K30X3]).
The GIP peptide analogue of any one of the preceding claims, wherein the amino acid in position 18 is a Lysine, and wherein said fatty acid molecule is attached to the epsilon-amino group of the lysine at position 18 of SEQ ID NO:
- (hGIP5-30, [K16R, H18X2, K30X3]) and SEQ ID NO:
- (hGIP3-30, [K16R, H18X2, K30X3]), or a functional variant thereof.
A glucose-dependent insulinotropic peptide (GIP) analogue consisting of SEQ ID NO:
- (hGIP10-30):
- 10 11 12 13 14 15 16 17 18 19 20 21
- Y - S - I - A - M - D - K - I - H - Q - Q - D -
- 22 23
- F - V
- 24 25 26 27 28 29 30
- N - W - L - L - A - Q - K
- wherein said GIP peptide analogue optionally further comprises:
- the peptide D at the N-terminus (hGIP9-30, SEQ ID NO:),
- the dipeptide S-D at the N-terminus (hGIP8-30, SEQ ID NO:),
- the tripeptide I-S-D at the N-terminus (hGIP7-30, SEQ ID NO:),
- the tetrapeptide F-I-S-D at the N-terminus (hGIP6-30, SEQ ID NO:),
- or a functional variant thereof, wherein said variant has 1 to 4 individual amino acid substitutions at any amino acid residue of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30),
- wherein said GIP peptide analogue is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 10 to 29 of any one SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof comprising between 1 and 4 individual amino acid substitutions, with or without a linker.
The GIP peptide analogue of any one of the preceding claims, wherein the H at position 18 of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof, is substituted with any amino acid, such as substituted with an amino acid selected from the group consisting of A, R, K and Orn.
The GIP peptide analogue of any one of the preceding claims, wherein the K at position 30 of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof, is substituted with any amino acid, such as substituted with an amino acid selected from the group consisting of E and R.
The GIP peptide analogue of any one of the preceding claims, a fatty acid molecule is attached to the side chain amino group of the amino acid at position 18 of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof, wherein H at position 18 has been substituted with K or Orn in any one of SEQ ID NO:
- SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof.
The GIP peptide analogue of any one of the preceding claims, wherein said functional variant has 1 individual amino acid substitution at any amino acid residue of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), such as 2 individual amino acid substitutions, such as 3 individual amino acid substitutions, for example 4 individual amino acid substitutions at any amino acid residue of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30).
The GIP peptide analogue of any one of the preceding claims, wherein said fatty acid molecule is attached to the epsilon-amino group of the K at position 18 of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof.
The GIP peptide analogue of any one of the preceding claims, wherein said fatty acid molecule is attached to the epsilon-amino group of the Orn at position 18 of any one of SEQ ID NO:
- (hGIP10-30), SEQ ID NO:
- (hGIP9-30), SEQ ID NO:
- (hGIP8-30), SEQ ID NO:
- (hGIP7-30), and SEQ ID NO:
- (hGIP6-30), or a functional variant thereof.
A glucose-dependent insulinotropic peptide (GIP) analogue consisting of SEQ ID NO:
- (hGIP3-30 [H18X2, K30X3]):
- 3 4 5 6 7 8 9 10 11 12 13 14
- E - G - T - F - I - S - D - Y - S - I - A - M -
- 15 16 17
- D - K - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - D - F - V - N - W - L - L - A - Q - X3
- wherein said amino acid X2 may be selected from a group consisting of K and Orn,
- wherein said amino acid X3 may be selected from a group consisting of R and E,
- or a functional variant thereof having 1 to 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 17 and 19 to 29 of SEQ ID NO:
- (hGIP3-30 [H18X2, K30X3]),
- wherein said peptide is modified by attaching at least one fatty acid molecule at the amino acid at position 18 of SEQ ID NO:
- (hGIP3-30 [H18X2, K30X3]), or a functional variant thereof.
A glucose-dependent insulinotropic peptide (GIP) analogue consisting of SEQ ID NO:
- (hGIP3-30 [D9E, D15E, H18X2, D21E, N24Q]):
- 3 4 5 6 7 8 9 10 11 12 13 14
- E - G - T - F - I - S - E - Y - S - I - A - M -
- 15 16 17
- E - K - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - E - F - V - Q - W - L - L - A - Q - K
- wherein said amino acid X2 may be selected from a group consisting of K and Orn,
- or a functional variant thereof having 1 to 4 individual amino acid substitutions at any one of positions 3 to 30 of SEQ ID NO:
- (hGIP3-30 [D9E, D15E, H18X2, D21E, N24Q]),
- wherein said peptide is modified by attaching at least one fatty acid molecule at the amino acid at position 18 of SEQ ID NO:
- (hGIP3-30 [D9E, D15E, H18X2, D21E, N24Q]), or a functional variant thereof.
A glucose-dependent insulinotropic peptide (GIP) analogue consisting of SEQ ID NO:
- (hGIP3-30 [T5A, S11A, I12A, H18X2, N24A]):
- 3 4 5 6 7 8 9 10 11 12 13 14
- E - G - A - F - I - S - E - Y - A - A - A - M -
- 15 16 17
- E - K - I
- 18 19 20 21 22 23 24 25 26 27 28 29 30
- X2 - Q - Q - E - F - V - A - W - L - L - A - Q - K
- wherein said amino acid X2 may be selected from a group consisting of K and Orn,
- or a functional variant thereof having 1 to 4 individual amino acid substitutions at any one of positions 3 to 30 of SEQ ID NO:
- (hGIP3-30 [T5A, 511A, I12A, H18X2, N24A]),
- wherein said peptide is modified by attaching at least one fatty acid molecule at the amino acid at position 18 of SEQ ID NO:
- (hGIP3-30 [T5A, S11A, I12A, H18X2, N24A]), or a functional variant thereof.
The GIP peptide analogue according to any one of the preceding claims, wherein said GIP peptide analogue is an antagonist of GIPR.
The GIP peptide analogue according to any one of the preceding claims, wherein said GIP peptide analogue inhibits GIPR activity of at least 80%, such as of at least 85%, such as of at least 90%, such as of at least 95%, such as of about 100%.
The GIP peptide analogue according to any one of the preceding claims, wherein said GIP peptide analogue inhibits GIPR activity of at least 80%, such as of at least 85%, such as of at least 90%, such as of at least 95%, such as of about 100%, wherein inhibition of GIPR activity is determined as a decrease in intracellular cAMP.
The GIP peptide analogue according to any one of the preceding claims, wherein said GIP peptide analogue has a GIPR antagonistic potency corresponding to an IC50 value of 50 nM or less.
The GIP peptide analogue of any one of the preceding claims, wherein a fatty acid molecule is not attached at the amino acid residue at position 3 of said GIP peptide analogue.
The GIP peptide analogue of any one of the preceding claims, wherein a fatty acid molecule is not attached at the N-terminal amino group of the most N-terminal amino acid residue of said GIP peptide analogue.
The GIP peptide analogue of any one of the preceding claims, wherein the GIP peptide analogue has a free N-terminus.
The GIP peptide analogue of any one of the preceding claims, wherein said peptide has an amino acid sequence selected from the group consisting of:
- PGTFISDYSIAMDRIKQQDFVNWLLAQR,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR
- TFISDYSIAMDRIKQQDFVNWLLAQR,
- TFISDYSIALDRIKQQDFVNWLLAQR,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR,
- YSIAMDKIKQQDFVNWLLAQK,
- DYSIAMDKIKQQDFVNWLLAQK,
- SDYSIAMDKIKQQDFVNWLLAQK,
- ISDYSIAMDKIKQQDFVNWLLAQK,
- FISDYSIAMDKIKQQDFVNWLLAQK,
- TFISDYSIAMDKIKQQDFVNWLLAQE,
- TFISEYSIAMEKIKQQEFVQWLLAQK,
- AFISDYAAAMDKIKQQDFVAWLLAQK,
- EGTFISEYSIAMEKIKQQEFVQWLLAQK
- or a variant thereof comprising 1 to 2 individual amino acid substitutions.
The GIP peptide analogue of any one of the preceding claims, wherein said peptide is C-terminally amidated (—NH2) or C-terminally carboxylated (—COOH).
The GIP peptide analogue of any one of the preceding claims, wherein said peptide is C-terminally carboxylated (—COOH).
The GIP peptide analogue of any one of the preceding claims, wherein said fatty acid molecule is a straight-chain fatty acid.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule is a branched fatty acid.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule is a monoacyl fatty acid molecule, comprising one fatty acid.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule is a diacyl fatty acid molecule.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises an acyl group of the formula CH3(CH2)nCO—, wherein n is in an integer from 4 to 24.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises one or more acyl groups selected from the group consisting of CH3(CH2)6CO—, CH3(CH2)8CO—, CH3(CH2)10CO—, CH3(CH2)12CO—, CH3(CH2)14CO—, CH3(CH2)16CO—, CH3(CH2)18CO—, CH3(CH2)20CO— and CH3(CH2)22CO—.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises an acyl group selected from the group consisting of CH3(CH2)10CO— (lauryl, C12), CH3(CH2)12CO— (myristoyl, C14), CH3(CH2)14CO— (palmitoyl, C16), CH3(CH2)16CO— (stearyl, C18), CH3(CH2)18CO— (arachidyl, C20) and CH3(CH2)20CO— (behenyl, C22).
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises two acyl groups individually selected from the group consisting of HOOC—CH3(CH2)10CO— (dodecanoyl, C12), HOOC—CH3(CH2)12CO— (1-tetradecanoyl, C14), HOOC—CH3(CH2)14CO— (hexadecanoyl, C16), HOOC—CH3(CH2)15CO— (15-carboxy-pentadecanoyl, C17), HOOC—CH3(CH2)16CO— (octadecanoyl, C18), HOOC—CH3(CH2)17CO— (17-carboxy-heptadecanoyl, C19), HOOC—CH3(CH2)18CO— (eicosanoyl, C20), HOOC—CH3(CH2)19CO— (19-carboxy-nonadecanoyl, C21) and HOOC—CH3(CH2)20CO— (behenyl, C22).
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises an acyl group of the formula COOH(CH2)nCO— (dicarboxylic acid), wherein n is an integer from 4 to 24.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises an acyl group selected from the group consisting of COOH(CH2)14CO—, COOH(CH2)16CO—, COOH(CH2)18CO— and COOH(CH2)20CO—.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises or consists of COOH(CH2)14CO—.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises or consists of COOH(CH2)16CO—.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule comprises or consists of COOH(CH2)18CO—.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule is attached to the epsilon amino group of the side chain of an amino acid residue of said GIP peptide analogue directly.
The GIP peptide analogue according to any of the preceding claims, wherein said fatty acid molecule is attached to an amino acid residue via a linker.
The GIP peptide analogue according to any of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker in such a way that a carboxyl group of the linker forms an amide bond with an amino group of the fatty acid molecule.
The GIP peptide analogue according to any of the preceding claims, wherein said linker comprises one or more moieties individually selected from the group consisting of:
- a. one or more an α,ω-amino acids,
- b. one or more amino acids selected from the group consisting of succinic acid, Lys, Glu, Asp,
- c. 4-Abu,
- d. y-aminobuturic acid
- e. a dipeptide, such as a dipeptide wherein the C-terminal amino acid residue is Lys, His or Trp, preferably Lys, and wherein the N-terminal amino acid residue is selected from the group comprising Ala, Arg, Asp, Asn, Gly, Glu, Gln, Ile, Leu, Val, Phe and Pro, such as Gly-Lys,
- f. one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparagyl, β-alanyl and glycyl, and
- g. γ-glutamic acid-[8-amino-3,6-dioxaoctanoic acid]n (γGlu-AEEAcn), wherein n is an integer between 1 and 50, such as an integer between 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50.
The GIP peptide analogue according to any of the preceding claims, wherein said linker comprises one or more moieties individually selected from the group consisting of:
- a. α-amino acid, γ-amino acid or ω-amino acid,
- b. one or more amino acids selected from the group consisting of succinic acid, Lys, Glu, Asp,
- c. one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagyl), β-Ala (β-alanyl) and Gly, and
- d. [8-amino-3,6-dioxaoctanoic acid]n (AEEAcn), wherein n is an integer between 1 and 50, such as an integer between 1-4, 1-3 or 1-2.
The GIP peptide analogue of any one of the preceding claims, wherein said linker comprises a γ-Glu, one or more 8-amino-3,6-dioxaoctanoic acid (AEEAc), or combinations thereof.
The GIP peptide analogue of any one of the preceding claims, wherein said linker comprises or consists of a γ-Glu.
The GIP peptide analogue of any one of the preceding claims, wherein said linker comprises or consists of a [8-amino-3,6-dioxaoctanoic acid]n (AEEAc)n, wherein n is an integer between 1 and 50, such as an integer between 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, preferably wherein n is 1, 2 or 3.
The GIP peptide analogue of any one of the preceding claims, wherein said linker comprises or consists of a γ-Glu and one AEEAc, such as a γ-Glu and two AEEAc, for example a γ-Glu and three AEEAc.
The GIP peptide analogue of any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker, and wherein the combination of linker and fatty acid is selected from the group consisting of:
- i. Hexadecanoyl-γ-Glu-
- ii. Hexadecanoyl-γ-Glu-γ-Glu-
- iii. Hexadecanoyl-γ-Glu-AEEAc-
- iv. Hexadecanoyl-γ-Glu-AEEAc-AEEAc-
- v. Hexadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc-
- vi. [15-carboxy-pentadecanoyl]-γ-Glu-
- vii. [15-carboxy-pentadecanoyl]-γ-Glu-γ-Glu-
- viii. [15-carboxy-pentadecanoyl]-γ-Glu-AEEAc-
- ix. [15-carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc-
- x. [15-carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc-
- xi. Octadecanoyl-γ-Glu-
- xii. Octadecanoyl-γ-Glu-γ-Glu-
- xiii. Octadecanoyl-γ-Glu-AEEAc-
- xiv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-
- xv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc-
- xvi. [17-carboxy-heptadecanoyl]-γ-Glu-
- xvii. [17-carboxy-heptadecanoyl]-γ-Glu-γ-Glu-
- xviii. [17-carboxy-heptadecanoyl]-γ-Glu-AEEAc-
- xix. [17-carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-
- xx. [17-carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc-
- xxi. Eicosanoyl-γ-Glu-
- xxii. Eicosanoyl-γ-Glu-γ-Glu-
- xxiii. Eicosanoyl-γ-Glu-AEEAc-
- xxiv. Eicosanoyl-γ-Glu-AEEAc-AEEAc-
- xxv. Eicosanoyl-γ-Glu-AEEAc-AEEAc-AEEAc-
- xxvi. [19-carboxy-nonadecanoyl]-γ-Glu-
- xxvii. [19-carboxy-nonadecanoyl]-γ-Glu-γ-Glu-
- xxviii. [19-carboxy-nonadecanoyl]-γ-Glu-AEEAc-
- xxix. [19-carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-
- xxx. [19-carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc-.
The GIP peptide analogue of any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker, and wherein the combination of linker and fatty acid is selected from the group consisting of:
- i. [15-Carboxy pentadecanoyl-yGlu
- ii. [17-carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-, and
- iii. [17-carboxy-heptadecanoyl]-yGlu-yGlu
The GIP peptide analogue of any one of the preceding claims selected from the group consisting of peptides having amino acid sequences consisting of:
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-NH2-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-(γ-Glu)-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-NH2-(γ-Glu)-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-( AEEAc +γ-Glu)-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-NH2-( AEEAc +γ-Glu)-C16-
- diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc +γ-Glu)-C16-diacid/K18,
- PGTFISDYSIAMDRIKQQDFVNWLLAQR-NH2-(2x AEEAc +γ-Glu)-C16-diacid
- /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR-C16-diacid/K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR-NH2-C16-diacid/K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR-(γ-Glu)-C16-diacid /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-(γ-Glu)-C16-diacid, /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR-( AEEAc -γ-Glu)-C16-diacid /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-( AEEAc -γ-Glu)-C16-diacid
- /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR-(2 AEEAc -γ-Glu-)C16-diacid /K18,
- GGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-(2x AEEAc -γ-Glu-)C16-diacid
- /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-C18-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-(γ-Glu)-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-(γ-Glu)-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-( AEEAc -γ-Glu)-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-( AEEAc -γ-Glu)-C16-diacid
- /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc -γ-Glu)-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR- NH2-(2x AEEAc G-γ-Glu)-C16-
- diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc -γ-Glu)-C18-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-( AEEAc -γ-Glu)-C16-diacid /K18,
- SGTFISDYSIAMDRIKQQDFVNWLLAQR-(3x AEEAc -γ-Glu)-C18-diacid /K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-C16-diacid /K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-C18-diacid /K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc -γ-Glu)-C16-
- diacid/K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc -γ-Glu)-C18-
- diacid/K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-(3x AEEAc -γ-Glu)-C16-
- diacid/K18,
- pyroEGTFISDYSIAMDRIKQQDFVNWLLAQR-(3x AEEAc -γ-Glu)-C18-
- diacid/K18,
- TFISDYSIALDRIKQQDFVNWLLAQR-(γ-Glu)-C16-diacid/K18,
- TFISDYSIALDRIKQQDFVNWLLAQR-( AEEAc +γ-Glu)-C16-diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-( AEEAc +γ-Glu)-C16-diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-(AEEAc +γ-Glu)-C18-diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc G+γ-Glu)-C16-
- diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-(2x AEEAc +γ-Glu)-C18-diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-(3x AEEAc +γ-Glu)-C16-diacid/K18,
- EGTFISDYSIAMDRIKQQDFVNWLLAQR-(3x AEEAc +γ-Glu)-C18-diacid/K18,
- YSIAMDKIKQQDFVNWLLAQK-C16-diacid/K18,
- DYSIAMDKIKQQDFVNWLLAQK-C16-diacid/K18,
- SDYSIAMDKIKQQDFVNWLLAQK-C16-diacid/K18,
- ISDYSIAMDKIKQQDFVNWLLAQK-C16-diacid/K18,
- FISDYSIAMDKIKQQDFVNWLLAQK-C16-diacid/K18,
- TFISDYSIAMDKIKQQDFVNWLLAQE-C16-diacid/K18,
- TFISEYSIAMEKIKQQEFVQWLLAQK-C16-diacid/K18,
- AFISDYAAAMDKIKQQDFVAWLLAQK-C16-diacid/K18, and
- EGTFISEYSIAMEKIKQQEFVQWLLAQK(NH2)- 2xPEG+yGlu-C18-diacid/K18
- or a variant thereof having 1 or 2 individual amino acid substitutions.
The GIP peptide analogue according to any of the preceding claims for use in a method of inhibiting or reducing one or more of i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and/or fatty acid incorporation, vi) high or increased expression or activity of a GIPR, vii) post-prandial GIP release, viii) serum levels of free fatty acids and/or triglycerides, ix) GIP-induced appetite increases, x) GIP-induced reduction in energy expenditure, xi) GIP-induced increase in absorption of nutrients from the gut, xii) GIP-induced decrease in GLP-1's appetite suppressive effect, xiii) GIP-induced leptin resistance
The GIP peptide analogue according to any of the preceding claims for use in a method of treating a condition selected from the group consisting of metabolic syndrome, obesity, over-weight, an obesity-related disorder, pre-diabetes (impaired fasting glucose), diabetes mellitus (type I and type 2), a diabetes-related disorder, insulin resistance, elevated fasting glucose (hyperglycemia), elevated fasting serum triglyceride level (VLDL triglyceride), low high-density lipoprotein (HDL) levels, a fatty acid metabolism disorder, a cardiovascular disease, elevated blood pressure and atherosclerosis.
Dependencies are inferred from the claim text.