Glucagon-like peptide-1 analogs
Disclosed are glucagon-like peptide-1 (GLP-1) compounds with modifications at one or more of the following positions: 11, 12, 16, 22, 23, 24, 25, 27, 30, 33, 34, 35, 36, or 37. Methods of treating these GLP-1 compounds are also disclosed.
1. An isolated GLP-1 compound comprising the amino acid sequence of formula 1 (SEQ ID NO:1)
(SEQ ID NO: 1)
His-Xaa 8 -Glu-Gly-Xaa 11 -Xaa 12 -Thr-Ser-Asp-Xaa 16 -
Ser-Ser-Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Xaa 24 -Ala-Xaa 26 -
Xaa 27 -Phe-Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 -
Xaa 36 -R Formula 1
wherein:
Xaa 8 is: Gly, or Val;
Xaa 11 is: Asp, Glu, Arg, Thr, Ala, Lys, or His;
Xaa 12 is: His, Trp, Phe, or Tyr;
Xaa 16 is: Leu, Ser, Thr, Trp, His, Phe, Asp, Val, Tyr, Glu, or Ala;
Xaa 22 is: Asp, Glu, Gln, Asn, Lys, Arg, Cys, or Cysteic Acid;
Xaa 23 is: His, Asp, Lys, Glu, Gln, or Arg;
Xaa 24 is: Glu, Arg, Ala, or Lys;
Xaa 26 is: Trp, Tyr, Phe, Asp, Lys, Glu, or His;
Xaa 27 is: Ala, Glu, His, Phe, Tyr, Trp, Arg, or Lys;
Xaa 30 is: Ala, Glu, Asp, Ser, or His;
Xaa 33 is: Asp, Arg, Val, Lys, Ala, Gly, or Glu;
Xaa 34 is: Glu, Lys, or Asp;
Xaa 35 is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe, Asp, Gly, Pro, His, or Glu;
Xaa 36 is: Thr, Ser, Asp, Trp, Tyr, Phe, Arg, Glu, or His;
R is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr, Phe, His, —NH2, Gly, Gly-Pro, or Gly-Pro-NH 2 , or is deleted,
and wherein the GLP-1 compound demonstrates insulinotropic activity.
2. The GLP-1 compound of claim 1 wherein Xaa 22 is aspartic acid, glutamic acid, lysine, or arginine.
3. The GLP-1 compound of claim 2 wherein Xaa 22 is glutamic acid.
4. An isolated GLP-1 compound comprising the amino acid sequence of formula II (SEQ ID NO:2):
(SEQ ID NO: 2)
His-Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-
Ser-Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -Glu-Phe-
Ile-Xaa 30 -Trp-Leu-Val-Lys-Xaa 35 -Arg-R formula II
wherein:
Xaa 8 is: Gly, or Val;
Xaa 12 is: His, Trp, Phe, or Tyr;
Xaa 16 is: Leu, Ser, Thr, Trp, His, Phe, Asp, Val, Glu, or Ala;
Xaa 22 is: Asp, Glu, Gln, Asn, Lys, Arg, Cys, or Cysteic Acid;
Xaa 23 is: His, Asp, Lys, Glu, or Gln;
Xaa 26 is: Asp, Lys, Glu, or His;
Xaa 30 is: Ala, Glu, Asp, Ser, or His;
Xaa 35 is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe, Asp, Gly, Pro, His, or Glu;
R is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr, Phe, His, —NH 2 , Gly, Gly-Pro, or Gly-Pro-NH 2 , or is deleted,
and wherein the GLP-1 compound demonstrates insulinotropic activity.
5. The GLP-1 compound of claim 4 wherein Xaa 22 is aspartic acid, glutamic acid, lysine, or arginine.
6. The GLP-1 compound of claim 5 wherein Xaa 22 is glutamic acid.
7. An isolated GLP-1 compound comprising the amino acid sequence of formula III (SEQ ID NO:3):
(SEQ ID NO: 3)
His-Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Lys-Xaa 27 -Phe-Ile-
Xaa 30 -Trp-Leu-Val-Lys-Gly-Arg-R formula III
wherein:
Xaa 8 is: Gly, or Val;
Xaa 22 is: Asp, Glu, Gln, Asn, Lys, Arg, Cys, or Cysteic Acid;
Xaa 23 is: His, Asp, Lys, Glu, or Gln;
Xaa 27 is: Ala, Glu, His, Phe, Tyr, Trp, Arg, or Lys
Xaa 30 is: Ala, Glu, Asp, Ser, or His;
R is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr, Phe, His, —NH 2 , Gly, Gly-Pro, or Gly-Pro-NH 2 , or is deleted,
and wherein the GLP-1 compound demonstrates insulinotropic activity.
8. The GLP-1 compound of claim 7 wherein Xaa 22 is aspartic acid, glutamic acid, lysine, or arginine.
9. The GLP-1 compound of claim 8 wherein Xaa 22 is glutamic acid.
10. An isolated GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 4:
(SEQ ID NO: 4)
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Xaa 22 -Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-
Trp-Leu-Val-Lys-Gly-Arg-R
wherein:
Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine and α-methyl-histidine;
Xaa 8 is glycine or valine;
Xaa 22 is aspartic acid, glutamic acid, glutamine, asparagine, lysine, arginine, cysteine, or cysteic acid; and
R is NH 2 or Gly(OH),
and wherein the GLP-1 compound demonstrates insulinotropic activity.
11. The GLP-1 compound of claim 10 wherein Xaa 22 is lysine, aspartic acid, glutamic acid or arginine.
12. The GLP-1 compound of claim 11 wherein Xaa 7 is L-histidine, Xaa 8 is glycine or valine and R is Gly(OH).
13. The GLP-1 compound of claim 1 , wherein the GLP-1 compound is selected from the group consisting of: Val 8 -Glu 22 -GLP-1(7–37)OH (SEQ ID NO: 5); Val 8 -Asp 22 -GLP-1(7–37)OH (SEQ ID NO: 6); Val 8 -Arg 22 -GLP-1(7–37)OH (SEQ ID NO: 7); and Val 8 -Lys 22 -GLP-1(7–37)OH (SEQ ID NO: 8).
14. The GLP-1 compound of claim 13 wherein the GLP-1 compound is Val 8 -Glu 22 -GLP-1(7–37)OH (SEQ ID NO: 5).