Peptide dual agonists of GIPR and GLP2R

1. A peptide dual agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and of the GLP2R (glucagon-like peptide-2 receptor), said peptide comprising the sequence:

(SEQ ID NO: 21)

HX 20 X 21 GTFISDYSTILDNLAARDFX 22 NWLX 23 X 24 X 25 KX 26 X 27 X 28 ,

wherein X 20 is selected from A, V and G,

X 21 is selected from D and E,

X 22 is selected from I and V,

X 23 is selected from I and L,

X 24 is selected from Q and A,

X 25 is selected from T and Q,

X 26 is selected from I and G,

X 27 is selected from T and K, and

X 28 is selected from D and K.

2. A peptide dual agonist of the GIPR and of the GLP2R, said peptide comprising an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 1)

HAEGTFISDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 2)

HAEGTFISDYSTILDNLAARDFINWLIQTKITDNDWKHNITQ,

(SEQ ID NO: 3)

HADGTFISDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 4)

HAEGSFISDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 5)

HAEGTFSDEYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 6)

HAEGTFISDMNTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 7)

HAEGTFISDYSIAMDKLAARDFINWLIQTKITD,

(SEQ ID NO: 9)

HAEGTFISDYSTILDNLAARDFVNWLLAQKITD,

(SEQ ID NO: 10)

HAEGTFISDYSTILDNLAARDFINWLIQTKGKK,

(SEQ ID NO: 11)

HGDGTFISDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 12)

HVDGTFISDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 13)

HADGTFSSDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 14)

HADGTFIDDYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 15)

HADGTFISEYSTILDNLAARDFINWLIQTKITD,

(SEQ ID NO: 16)

HADGTFISDYSTILDNLAARDFINWLIQTKGTD,

(SEQ ID NO: 17)

HADGTFISDYSTILDNLAARDFINWLIQTKIKD,

(SEQ ID NO: 18)

HADGTFISDYSTILDNLAARDFINWLIQTKITK,

(SEQ ID NO: 19)

HADGTFISDYSTILDNLAARDFINWLIQTKGKK,

(SEQ ID NO: 26)

HADGTFSSDYSTILDNLAAKDFINWLIQTKITD,

(SEQ ID NO: 27)

HADGTFISDYSKILDNLAARDFINWLIQTKITK,

(SEQ ID NO: 28)

HADGTFISDYSTIKDNLAARDFINWLIQTKITK,

(SEQ ID NO: 29)

HADGTFISDYSTILDKLAARDFINWLIQTKITK,

(SEQ ID NO: 30)

HADGTFISDYSTILDNLKARDFINWLIQTKITK,

(SEQ ID NO: 31)

HADGTFISDYSTILDNLAAKDFINWLIQTKITK,

and

(SEQ ID NO: 32)

HADGTFISDYSTILDNLAARDFINWLIQTKGKKNDWKHNITQ.

3. The peptide dual agonist according to claim 2 , wherein said peptide further comprises additional amino acids at the C-terminus.

4. The peptide dual agonist according to claim 3 , wherein said additional amino acids at the C-terminus is NDWKHNITQ (SEQ ID NO:25), or a variant or fragment of SEQ ID NO:25.

5. The peptide dual agonist according to claim 2 , wherein said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues of any one of SEQ ED NOs: 1-7, 9-19 and 26-32.

6. The peptide dual agonist according to claim 2 , wherein said peptide is modified by attaching at least one fatty acid molecule at one or more lysine residues.

7. The peptide dual agonist according to claim 2 , wherein said fatty acid molecule is a monoacyl fatty acid molecule, comprising one fatty acid.

8. The peptide dual agonist according to claim 2 , wherein said fatty acid molecule is a diacyl fatty acid molecule.

9. The peptide dual agonist according to claim 2 , wherein said fatty acid molecule comprises an acyl group of the formula CH 3 (CH 2 ) n CO—, wherein n is an integer from 4 to 24.

10. The peptide dual agonist according to claim 2 , wherein said fatty acid molecule comprises an acyl group selected from the group consisting of CH 3 (CH 2 ) 10 CO— (lauryl, C12), CH 3 (CH 2 ) 12 CO— (myristoyl, C14), CH 3 (CH 2 ) 14 O— (palmitoyl, C16) and CH 3 (CH 2 ) 16 CO— (stearyl, C18).

11. The peptide dual agonist according to claim 2 , said peptide comprising a peptide selected from the group consisting of:

(SEQ ID NO: 18)

H(C16/1)ADGTFISDYSTILDNLAARDFINWLIQTKITK,

(SEQ ID NO: 18)

HADGTFISDYSTILDNLAARDFINWLIQTK(C12/30)ITK,

(SEQ ID NO: 18)

HADGTFISDYSTILDNLAARDFINWLIQTK(C16/30)ITK,

(SEQ ID NO: 18)

HADGTFISDYSTILDNLAARDFINWLIQTKITK(C12/33),

(SEQ ID NO: 18)

HADGTFISDYSTILDNLAARDFINWLIQTKITK(C16/33),

(SEQ ID NO: 19)

HADGTFISDYSTILDNLAARDFINWLIQTKGK(C12/32)K,

(SEQ ID NO: 19)

HADGTFISDYSTILDNLAARDFINWLIQTKGK(C16/32)K,

(SEQ ID NO: 26)

HADGTFSSDYSTILDNLAAK(C16/20)DFINWLIQTKITD,

(SEQ ID NO: 13)

H(C16/1)ADGTFSSDYSTILDNLAARDFINWLIQTKITD

and

(SEQ ID NO: 13)

HADGTFSSDYSTILDNLAARDFINWLIQTK(C16/30)ITD.

12. The peptide dual agonist according to claim 2 , said peptide comprising a peptide of sequence HADGTFISDYSTILDKLAARDFINWLIQTKITK (SEQ ID NO:29).

13. The peptide dual agonist according to claim 2 , said peptide comprising a peptide of sequence HADGTFISDYSTILDKLAARDFINWLIQTKITK (SEQ ID NO:29)), wherein said peptide further comprises additional amino acids at the C-terminus.

14. The peptide dual agonist according to claim 2 , wherein said peptide

a. binds to GIPR and GLP2R, and/or

b. activates GIPR and GLP2R, and/or

c. stimulates GIPR- and GLP2R-mediated cAMP production, and/or

d. inhibits bone resorption, and/or

e. stimulates bone formation.

15. The peptide dual agonist according to claim 2 , wherein said peptide is capable of:

activating the GIPR with an efficacy (E max values) which is at least 65% of an efficacy by which native GIP activates the GIPR; and

activating the GLP2R with an efficacy (E max values) which is at least 65% of an efficacy by which native GLP-2 activates the GLP2R.

16. A nucleic acid construct encoding a peptide dual agonist according to claim 2 .

17. A delivery vehicle comprising the nucleic acid construct according to claim 16 .

18. A method of inhibiting bone resorption and/or stimulating bone formation comprising administering a therapeutically effective amount of a peptide dual agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and of the GLP2R (glucagon-like peptide-2 receptor), said peptide comprising the sequence:

(SEQ ID NO: 21)

HX 20 X 21 GTFISDYSTILDNLAARDFX 22 NWLX 23 X 24 X 25 KX 26 X 27 X 28 ,

wherein X 20 is selected from A, V and G,

X 21 is selected from D and E,

X 22 is selected from I and V,

X 23 is selected from I and L,

X 24 is selected from Q and A,

X 25 is selected from T and Q,

X 26 is selected from I and G,

X 27 is selected from T and K, and

X 28 is selected from D and K.

19. A method of treating a bone disorder comprising administering a therapeutically effective amount of a peptide dual agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and of the GLP2R (glucagon-like peptide-2 receptor), said peptide comprising the sequence:

(SEQ ID NO: 21)

HX 20 X 21 GTFISDYSTILDNLAARDFX 22 NWLX 23 X 24 X 25 KX 26 X 27 X 28 ,

wherein X 20 is selected from A, V and G,

X 21 is selected from D and E,

X 22 is selected from I and V,

X 23 is selected from I and L,

X 24 is selected from Q and A,

X 25 is selected from T and Q,

X 26 is selected from I and G,

X 27 is selected from T and K, and

X 28 is selected from D and K.

20. The method according to claim 19 , wherein said bone disorder is selected from the group consisting of osteopenia, osteoporosis, severe osteoporosis, osteomalacia, rickets, osteitis fibrosa cystica (OFC) and Paget's disease of bone.