Incretin analogs and uses thereof

1. An incretin analog comprising:

YX 2 QGTFTSDYSIX 13 LDKX 17 AX 19 X 20 AFIEYLLX 28 X 29 GPSSX 34 APPPS,

wherein:

X 2 is Aib,

X 13 is L or αMeL,

X 17 is any amino acid with a functional group available for conjugation selected from the group consisting of K, C, E and D, and the functional group is conjugated to a C 16 -C 22 fatty acid,

X 19 is Q or A,

X 20 is Aib, αMeK, Q or H,

X 28 is E or A,

X 29 is G or Aib,

X 34 is G or Aib,

(SEQ ID NO:5), and

wherein the C-terminal amino acid is optionally amidated;

or a pharmaceutically acceptable salt thereof.

2. The incretin analog of claim 1 , wherein the amino acid with the functional group available for conjugation at position X 17 is K.

3. The incretin analog of claim 1 , wherein the amino acid with the functional group available for conjugation at position X 17 and the C 16 -C 22 fatty acid are conjugated by a linker between the amino acid and the fatty acid.

4. The incretin analog of claim 3 , wherein the linker comprises one to four amino acids.

5. The incretin analog of claim 4 , wherein the amino acids are Glu or γGlu.

6. The incretin analog of claim 3 , wherein the linker further comprises a structure of:

H—{NH—CH 2 —CH 2 [O—CH 2 —CH 2 ] m —O—(CH 2 ) p —CO} n —OH, wherein m is any integer from 1 to 12, n is any integer from 1 to 12, and p is 1 or 2.

7. The incretin analog of claim 3 , wherein the linker further comprises one to four (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties.

8. The incretin analog of claim 1 , wherein X 17 is a K chemically modified through conjugation to an epsilon-amino group of a K side-chain with the following structure:

(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γGlu) b -CO—(CH 2 ) c —CO 2 H, wherein a is 0, 1 or 2; b is 1 or 2; and c is an integer between 16 to 18.

9. The incretin analog of claim 8 , wherein a is 1.

10. The incretin analog of claim 8 , wherein b is 1.

11. The incretin analog of claim 8 , wherein c is 18.

12. The incretin analog of claim 1 , wherein X 13 is αMeL.

13. The incretin analog of claim 1 , wherein X 20 is Aib.

14. The incretin analog of claim 1 , wherein X 28 is E.

15. The incretin analog of claim 1 , wherein X 29 is G.

16. The incretin analog of claim 1 , wherein X 34 is G.

17. The incretin analog of claim 1 , wherein X 19 is Q.

18. The incretin analog of claim 8 , wherein a is 1, b is 1, c is 18, X 13 is αMeL, X 19 is Q, X 20 is Aib, X 28 is E, X 29 is G and X 34 is G.

19. An incretin analog having a formula selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:21 SEQ ID NO:23 and SEQ ID NO:25, or a pharmaceutically acceptable salt thereof.

20. A method of treating a disease selected from the group consisting of diabetes mellitus, obesity, fatty liver disease, non-alcoholic steatohepatitis, dyslipidemia and metabolic syndrome, the method comprising a step of:

administering to an individual in need thereof an effective amount of an incretin analog of claim 1 .

21. The method of claim 20 , wherein the disease is obesity or type II diabetes mellitus.

22. A pharmaceutical composition comprising:

an incretin analog of claim 1 ; and

a pharmaceutically acceptable carrier, diluent or excipient.

23. The method of claim 20 , wherein the disease is obesity.

24. The method of claim 20 , wherein the disease is type II diabetes mellitus.

25. The incretin analog of claim 19 , having a formula of SEQ ID NO: 17, or a pharmaceutically acceptable salt thereof.

26. An incretin analog having a formula

(SEQ ID NO:17) or a pharmaceutically acceptable salt thereof.