Co-agonists of the glucagon and GLP-1 receptors

1. A co-agonist peptide comprising a peptide selected from following peptides

SEQ

ID

NO:

Name

Sequence

 1

PD17

HSVGNFWSDYSKYLDSRRAQDFVQWLMLT-CONH 2

 2

PD18

HSQGTFTSDYSKYVEDRRAHDFVQWLMNT-CONH 2

 3

PD19

HSQGTFTSDYRKYLDERAAWDFVQWLMNT-CONH 2

 4

PD20

HSQGTFTSDYSKYLNSWMTQDFVQWLMNT-CONH 2

 5

PD21

HSQGTFTSDYSKYLDIGRAQDFVQWLLNT-CONH 2

 6

PD22

HSQGTFTSDYSKYLDSLMAQDFVQWLMST-CONH 2

 7

PD23

HSQGTFTSDYSKYLDWRRAQDFVQWLLNT-CONH 2

 8

PD24

HSQGTFTSDYIKLLDSRRAQDFVQWLMNT-CONH 2

 9

PD25

HSQGTFTSDYSKYLDARRAQDFVQWLIRT-CONH 2

10

PD26

HSQGTFTSDYSKYLDVRRAQDFVQWLMNT-CONH 2

11

PD27

HSQGTFTSDYSKYLDELRAYDFVQWLMNT-CONH 2

12

PD28

HSQGTFTSDYSKYLDYMRAYDFVQWLMNT-CONH 2

13

PD29

HSQGTFTSDYSKYLDSRRAHDFVQWLLNT-CONH 2

14

PD30

HSQGTFTSDYSKYLDSRRAQDFVQWLMNP-CONH 2

15

PD31

HSQGTFTSDYSKYLDSRRAQDFVQWLINY-CONH 2

16

PD32

INHEQWAFTSDYSKYLDSRRAQDFVQWLMNT-CONH 2

17

PD33

ASMFTFFSDYSKYLDSRRAQDFVQWLMLT-CONH 2

18

PD34

HSQGTFLSDYSKLLDSRRAQDFVQWLMQT-CONH 2

19

PD35

HSQGTFLHDYYYYLDSRRAQDFVQWLMDT-CONH 2

20

PD36

HSQGTFTSDYSKYLDSIRAQDFVQWLMDT-CONH 2

21

PD37

HSQGTFTSDYSKYLDNKRAQDFVQWLMQT-CONH 2

22

PD38

HSQGTFTSDYSKYLDSRRAQDFVDWLMNE-CONH 2

23

PD39

HSQGTFTSDYSKYLDSRRAQEFVEWLMDE-CONH 2

24

PD40

HSQGTFTSDYSKYLDSRRAQDFVQWLINT-CONH 2

25

PD41

KALGQFTFTSDYSKYLDSRRAQDFVQWLMNT-CONH 2

26

PD42

HSQGTFFHDYSKYLDSRRAQDFVQWLLNT-CONH 2

27

PD43

HSQGTFFSDYSHWLDSRRAQDFVQWLMNT-CONH 2

28

PD44

HSQGTFTSDYSKYLDWRRAQDFVQWLQNT-CONH 2

29

PD45

HSQGTFTSDYSKYLDSKRAHDFVQWLLNT-CONH 2

30

PD46

HSQGTFTSDYSKYLDSRRAQDFWIDLMNT-CONH 2

31

PD47

HSQGTFTSDYSKYLDSRRAQDFVMTSMNT-CONH 2

32

PD48

HSQGTFTSDYSKYLDSRRAQDFVDWLLNA-CONH 2

33

PD49

HSQGTFTSDYSKYLDSRRAQDFVEWLMNN-CONH 2

34

PD50

HSQGTFTSDYSKYLDSRRAQDFVDWLINS-CONH 2

35

PD51

HSHGTFTSDYSKYLDSRRAQDFVQWLMTT-CONH 2

36

PD52

HSQGIFFSDYSKYLDSRRAQDFVQWLMNT-CONH 2

37

PD53

HSQGTFLSDYSKYLDSRRAQDFVQWLMNT-CONH 2

38

PD54

HSQGTFTSDYSWYLDSRRAQDFVQWLMNT-CONH 2

39

PD55

HSQGTFTSDYSKYLDMQRAHDFVQWLMNT-CONH 2

40

PD56

HSQGTFTSDYSKYLDSRMAYDFVQWLMNT-CONH 2

41

PD57

HSQGTFTSDYSKYLDSRRAQDFVQWLLNQ-CONH 2

42

PD58

HSQGTFFSDYSKYLDSRRAQDFVQWLLET-CONH 2

43

PD59

HSQGTFTSDYSKYLDSRRAQDFVQWLLDS-CONH 2

wherein the L-Serine at position 2 is replaced with Val, Ile, Asp, Glu, Met, Trp, Asn, D-Ala, D-Ser, or α-aminoisobutyric acid (aib), the Tyrosine at position 10 is replaced with a Lysine residue conjugated to a fatty acid or fatty diacid via a linking moiety, wherein CONH 2 indicates the C-terminal amino acid carboxy group is amidated.

2. The co-agonist peptide of claim 1 , wherein the fatty acid or fatty diacid comprises 14 to 20 methylene groups.

3. The co-agonist peptide of claim 1 , wherein the fatty acid or fatty diacid comprises 16 carbon atoms.

4. The co-agonist peptide of claim 1 , wherein the linking moiety comprises a PEG 2 (8-amino-3,6-dioxaoctanoic acid) Gamma-Glutamic acid (γGlu), a γGlu, a γGluγGlu, or a PEG 2 PEG 2 γGlu.

5. A co-agonist peptide comprising a peptide selected from the following peptides

SEQ

ID

NO:

Name

Sequence

44

TP534

HsQGTFTSDK(γEγEC16)SKYLDNKRAQDFVQWLMQT-

CONH 2

45

TP535

HsQGTFTSDK(γEγEC16)SKYLDSRRAHDFVQWLLNT-

CONH 2

46

TP536

HsQGTFLSDK(γEγEC16)SKLLDSRRAQDFVQWLMQT-

CONH 2

47

TP552

HsQGTFLSDYSKLLDSRAAQDFVQWLLQT-CONH 2

48

TP559

HsQGTFTSDK(γEγEC16)SKYLDARAAHDFVQWLLNT-

CONH 2

49

TP572

HUQGTFTSDK(γEγEC16)

SKYLDSRRAHDFVQWLLNTKγE-CONH 2

50

TP573

HUQGTFTSDK(γEγEC16)

SKYLDARAAHDFVQWLLNTKγE-CONH 2

51

TP574

HUQGTFTSDK(γEγEC16)

SKYLDNKRAQDFVQWLMQTKγE-CONH 2

wherein U is aminoisobutyric acid, s is D-Ser, γE=γ-glutamic acid, and C16=—CO—(CH 2 ) 14 —CH 3 , and wherein CONH 2 indicates the C-terminal amino acid carboxy group is amidated.

6. A composition comprising one or more co-agonist peptides of claim 1 and a pharmaceutically acceptable carrier and/or pharmaceutically acceptable salt.

7. A method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of any one or more of the co-agonist peptides of claim 1 to treat the metabolic disease or disorder in the patient.

8. The method of claim 7 , wherein the metabolic disease or disorder comprises diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or obesity.

9. The method of claim 8 , wherein the diabetes comprises Type I diabetes, Type II diabetes, or gestational diabetes.

10. The method of claim 7 , wherein the patient has more than one metabolic disease or disorder.

11. The method of claim 10 , wherein the metabolic disease or disorder comprises, diabetes and NASH, NAFLD, or obesity; obesity and NASH or NAFLD; diabetes, NASH, and obesity; diabetes, NAFLD, and obesity; or diabetes and obesity.

12. A method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the composition of claim 6 to treat the metabolic disease or disorder in the patient.

13. The method of claim 12 , wherein the metabolic disease or disorder comprises diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or obesity.

14. The method of claim 12 , wherein the patient has more than one metabolic disease or disorder.

15. The method of claim 14 , wherein the metabolic disease or disorder comprises, diabetes and NASH, NAFLD, or obesity; obesity and NASH or NAFLD; diabetes, NASH, and obesity; diabetes, NAFLD, and obesity; or diabetes and obesity.

16. A method for treating a metabolic disease or disorder in a patient or individual comprising: administering to the patient or individual an effective amount of the composition of claim 6 and administering to the patient or individual an effective amount of a composition comprising an insulin or insulin analog to treat the metabolic disease or disorder in the patient or individual.

17. The method of claim 16 , wherein the insulin analog comprises insulin detemir, insulin glargine, insulin levemir, insulin glulisine, insulin degludec, or insulin lispro.

18. The method of claim 17 , wherein the metabolic disease or disorder comprises diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or obesity.

19. The method of claim 18 , wherein the diabetes comprises Type I diabetes, Type II diabetes, or gestational diabetes.

20. The method of claim 16 , wherein the patient has more than one metabolic disease or disorder selected from diabetes and NASH, NAFLD, or obesity; obesity and NASH or NAFLD; diabetes, NASH, and obesity; diabetes, NAFLD, and obesity; or diabetes and obesity.