Fusion proteins

1. A fusion protein comprising:

a) an insulin receptor agonist having the general formula Z 1 —Z 2 —Z 3 , wherein:

i) Z 1 is an insulin B-chain analog, comprising the amino acid sequence:

X 1 X 2 X 3 QHLCGSHLVEALX 4 LVCGERGFX 5 YX 6 X 7 X 8 X 9

 wherein X 1 is F, Q or A; X 2 is V or G; X 3 is N, K, D, G, Q, A or E; X 4 is E, Y, Q, or H; X 5 is H or F; X 6 is G, T, S, H, V or is absent; X 7 is G, E, P, K, D, S, H or is absent; X 8 is G, E, K, P, Q, D, H or is absent; X 9 is G, T, S, E, K, A or is absent, provided that the insulin B-chain analog includes at least one modification from the amino acid sequence of the B-chain of a molecule of human insulin at X 4 , X 5 , X 6 , X 7 , X 8 , or X 9 (SEQ ID NO:1);

ii) Z 2 is a first peptide linker comprising 5 to 10 amino acids, wherein at least 5 of said amino acids are G residues; and

iii) Z 3 is an insulin A-chain analog comprising the amino acid sequence:

GIVEQCCTSX 1 CSLX 2 QLENYCX 3 X 4

 wherein X 1 is T or I; X 2 is D, Y, Q or E; X 3 is G, N, S or A; and X 4 is any naturally occurring amino acid, or is absent, provided that if X 3 is N, then X 4 must be an amino acid other than G or N (SEQ ID NO:2);

b) a second peptide linker; and

c) a human IgG Fc region;

wherein the C-terminal residue of the insulin receptor agonist is directly fused to the N-terminal residue of the second peptide linker, and the C-terminal residue of the second peptide linker is directly fused to the N-terminal residue of the human IgG Fc region.

2. The fusion protein of claim 1 , wherein:

the insulin B-chain analog includes at least one modification from the amino acid sequence of the human insulin B-chain at X 4 or X 5 of SEQ ID NO:1; and

and the insulin A-chain analog includes at least one modification from the amino acid sequence of the human insulin A-chain at X 1 or X 2 of SEQ ID NO:2.

3. The fusion protein of claim 2 , wherein:

the insulin B-chain analog comprises the sequence of SEQ ID NO:1, wherein: X 1 is F; X 2 is V, X 3 is N or D; X 4 is E; X 5 is H; and

the insulin A-chain analog comprises the sequence of SEQ ID NO:2, wherein: X 1 is I or T; X 2 is D; X 3 is G; and X 4 is absent.

4. The fusion protein of claim 3 , wherein the insulin B-chain analog comprises the sequence of SEQ ID NO:1, wherein X 6 -X 9 are each G.

5. The fusion protein of claim 1 , wherein the first peptide linker comprises the following amino acid sequence:

X 1 GX 2 GGGG

wherein X 1 is G or is absent; and X 2 is G, S or is absent (SEQ ID NO:3).

6. The fusion protein of claim 5 , wherein X 1 and X 2 of SEQ ID NO:3 are G and S, respectively.

7. The fusion protein of claim 1 , wherein the insulin receptor agonist has the following amino acid sequence:

(SEQ ID NO: 5)

FVNQHLCGSHLVEALELVCGERGFHYGGGGGGSGGGGGIVEQCCTSTCSL

DQLENYCG.

8. The fusion protein of claim 1 , wherein the second peptide linker is a peptide having between 10 and 25 amino acids, wherein at least 50% of said amino acids are G residues.

9. The fusion protein of claim 8 , wherein the second peptide linker comprises a peptide having the sequence [GGGGX] n

wherein X is Q, E or S; and wherein n is 2-5 (SEQ ID NO: 26).

10. The fusion protein of claim 9 , wherein the second peptide linker comprises the following amino acid sequence:

GGGGX 1 GGGGX 2 GGGGX 3 GGGGX 4 X 5 X 6

X 1 is Q or E

X 2 is Q or E

X 3 is Q or E

X 4 is G, E, Q or is absent

X 5 is G or absent; and

X 6 is G or is absent

(SEQ ID NO:6).

11. The fusion protein of claim 1 , wherein the second peptide linker has the following amino acid sequence:

(SEQ ID NO: 7)

GGGGQGGGGQGGGGQGGGGG.

12. The fusion protein of claim 1 , wherein the human IgG Fc region is an Fc region from an IgG1, IgG2 or IgG4.

13. The fusion protein of claim 1 , wherein the human IgG Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10.