ANALOGS OF GLUCAGON EXHIBITING GIP RECEPTOR ACTIVITY
Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.
1 . A peptide comprising the sequence of X 1 X 2 X 3 GTFTSDX 10 SKYLX 15 X 16 X 17 X 18 X 19 X 20 X 21 FVQWLX 27 X 28 X 29 X 30 PSSGX 35 PPPS (SEQ ID NO: 140), wherein
X 1 corresponds to position 1 of native glucagon and
X 1 is selected from the group consisting of: Acetyl D-His, Acetyl D-Tyr, Acetyl D-Thio Ala, Acetyl Thio Ala, Acetyl D-Phe, Desamino Tyr, Desamino His, D-His, and D-Tyr;
X 2 is Ala or Gly,
X 3 is Gln;
X 10 is an amino acid covalently attached to a C12 to C18 acyl or alkyl group;
X 15 is Asp;
X 16 is Glu;
X 17 is Arg, His, or Gln;
X 18 is Ala;
X 19 is Ala;
X 20 is Gln;
X 21 is Asp;
X 27 is Leu;
X 28 is Glu;
X 29 is Gly;
X 30 is Gly
X 35 is Ala;
wherein the peptide exhibits agonist activity at the human GIP receptor and the human GLP-1 receptor and the human glucagon receptor.
2 . The peptide of claim 1 , wherein the amino acids at positions 1 and 2 of the peptide are a pair of amino acids selected from the group consisting of:
Position 1
Position 2
Acetyl D-His
Ala
Acetyl D-Tyr
Ala
Desamino Tyr
Ala
Acetyl D-Thio Ala
Ala
Acetyl Thio Ala
Ala
D-His
Ala
D-Tyr
Ala
Desamino His
Ala
Acetyl D-Phe
Ala
3 . The peptide of claim 1 , wherein the amino acid at position 10 is Lys and said Lys is covalently attached to a C12-C18 acyl group.
4 . An analog of the peptide of claim 1 comprising
a. a sequence of SEQ ID NO: 11 with up to 3 amino acid modifications relative to SEQ ID NO: 11;
b. a sequence of SEQ ID NO: 12 with up to 3 amino acid modifications relative to SEQ ID NO: 12,
c. a sequence of SEQ ID NO: 13 with up to 3 amino acid modifications relative to SEQ ID NO: 13,
d. a sequence of SEQ ID NO: 15 with up to 3 amino acid modifications relative to SEQ ID NO: 15,
e. a sequence of SEQ ID NO: 16 with up to 3 amino acid modifications relative to SEQ ID NO: 16, or
f. a sequence of SEQ ID NO: 22 with up to 3 amino acid modifications relative to SEQ ID NO: 22,
wherein the analog exhibits agonist activity at the human GIP receptor and the human GLP-1 receptor and the human glucagon receptor.
5 . A peptide consisting of the sequence of X 1 X 2 X 3 GTFTSDX 10 SKYLX 15 X 16 X 17 X 18 X 19 X 20 X 21 FVQWLX 27 X 28 X 29 X 30 PSSGX 35 PPPS-R (SEQ ID NO: 140), wherein
X 1 corresponds to position 1 of native glucagon and
X 1 is selected from the group consisting of: Acetyl D-His, Acetyl D-Tyr, Acetyl D-Phe, Desamino Tyr, Desamino His, D-His, and D-Tyr;
X 2 is Ala or Gly,
X 3 is Gln;
X 10 is Tyr;
X 15 is Asp;
X 16 is Glu;
X 17 is Arg, His, or Gln;
X 18 is Ala;
X 19 is Ala;
X 20 is Gln;
X 21 is Asp;
X 27 is Leu;
X 28 is Glu;
X 29 is Gly;
X 30 is Gly
X 35 is Ala; and
R is a C-terminal dipeptide consisting of X 40 X 41 wherein
X 40 is an amino acid covalently attached to a C12 to C18 acyl or alkyl group; and
X 41 is Gly,
wherein the peptide exhibits agonist activity at the human GIP receptor and the human GLP-1 receptor and/or the human glucagon receptor.
6 . The peptide of claim 5 , comprising at positions 1 and 2 a pair of amino acids selected from the group consisting of:
Position 1
Position 2
Acetyl D-His
Ala
Acetyl D-Tyr
Ala
Desamino Tyr
Ala
7 . The peptide of claim 5 , wherein said peptide consists of SEQ ID NO:
149, SEQ ID NO: 152, SEQ ID NO: 157, or SEQ ID NO: 159.
8 . A dimer or multimer comprising two or more peptides of claim 1 .
9 . A dimer or multimer comprising two or more peptides of claim 5 .
10 . A conjugate comprising the peptide of claim 1 and a conjugate moiety.
11 . A conjugate comprising the peptide of claim 5 and a conjugate moiety.
12 . A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
13 . A pharmaceutical composition comprising the peptide of claim 5 and a pharmaceutically acceptable carrier, diluent, or excipient.
14 . A method of reducing weight gain or inducing weight loss in a subject in need thereof, comprising administering to a patient in need thereof a pharmaceutical composition of claim 12 in an amount effective to reduce weight gain or induce weight loss.
15 . A method of treating diabetes, comprising administering to a patient in need thereof a pharmaceutical composition of claim 12 in an amount effective to lower blood glucose levels.
16 . A method of simultaneously stimulating the glucagon, GLP-1, and GIP receptors to reduce weight gain or inducing weight loss in a subject, comprising administering a peptide of claim 1 in an amount effective to reduce weight gain or induce weight loss in said subject.
17 . A method of simultaneously stimulating the glucagon, GLP-1, and GIP receptors to reduce weight gain or inducing weight loss in a subject, comprising administering a peptide SEQ ID NO: 12 in an amount effective to reduce weight gain or induce weight loss in said subject.
18 . A method of simultaneously stimulating the glucagon, GLP-1, and GIP receptors to treat diabetes, comprising administering a peptide of claim 1 in an amount effective to lower blood glucose levels in said subject.
19 . A method of simultaneously stimulating the glucagon, GLP-1, and GIP receptors to treat diabetes, comprising administering a peptide of SEQ ID NO: 12 in an amount effective to lower blood glucose levels in said subject.