Glucagon/GLP-1 receptor co-agonists

• US 9,309,301 B2
• Filed: 06/12/2012
• Issued: 04/12/2016
• Est. Priority Date: 06/22/2011
• Status: Expired due to Fees

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Inventors: Dimarchi, Richard D., Smiley, David L., Yang, Bin S.
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US14/127,469
• Publication Number:
  US 20140206607A1
• Time in Patent Office: 1,400 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G01N 2333/605 Glucagons
• CPC Class Codes: G01N 2800/042 Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 2800/2835 Movement disorders, e.g. Parkinson, Huntington, Tourette
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.

Claims

1. A peptide comprising

or a pharmaceutically acceptable salt thereof.

2. A variant peptide comprising the amino acid sequence of the peptide of claim 1 but differs in one or more of the following ways:

a. the variant peptide comprises an acylated amino acid or an alkylated amino acid;

b. an acylated amino acid or an alkylated amino acid is replaced with the corresponding amino acid of native glucagon (SEQ ID NO;

     1) at that position or a conservative substitution of the native amino acid, and optionally a new acylated or alkylated amino acid is introduced at a different position;

c. the variant peptide comprises an amino acid covalently attached to a hydrophilic moiety;

d. an amino acid covalently attached to a hydrophilic moiety is replaced with the corresponding amino acid of native glucagon (SEQ ID NO;

     1) at that position, and optionally a new amino acid covalently attached to a hydrophilic moiety is introduced at a different position;

e. the C-terminal amino acid of the variant peptide comprises a C-terminal amide in place of a C-terminal alpha carboxylate;

f. an amino acid at any of positions 1 through 29 is replaced with the corresponding amino acid of native glucagon (SEQ ID NO;

     1) at that position;

g. or any combinations thereof;

or a pharmaceutically acceptable salt thereof.

3. The variant peptide of claim 2, comprising (i) a hydrophilic moiety covalently attached to an amino acid at position 16, 17, 21, 24, 29, a position within a C-terminal extension, or at the C-terminus, (ii) a hydrophilic moiety covalently attached to an amino acid selected from the group consisting of:

Cys, Lys, Orn, homocysteine, and Ac-Phe, (iii) or a combination thereof.

4. The variant peptide of claim 3, wherein the hydrophilic moiety is a polyethylene glycol.

5. The variant peptide of claim 3, wherein the hydrophilic moiety is a polyethylene glycol having a molecular weight of 40 kda.

6. The variant peptide of any of claim 2, comprising (i) an acylated or alkylated amino acid at position 10;

(ii) an acylated or alkylated amino acid which an acylated or alkylated amino acid of Formula I, Formula II, or Formula III, optionally, wherein the amino acid of Formula I is Lys, or (iii) an acylated or alkylated amino acid, wherein the acyl group or alkyl group is covalently attached to the amino acid via a spacer, optionally, wherein the spacer is an amino acid or a dipeptide.

7. The variant peptide of claim 6, comprising an acylated or alkylated amino acid which comprises a C8 to C20 alkyl chain, a C12 to C18 alkyl chain, or a C14 or C16 alkyl chain.

8. The variant peptide of claim 6, wherein the spacer comprises one or two acidic residues.

9. The variant peptide of claim 2, wherein the (EC50 at the glucagon receptor)/(EC50 at the GLP-1 receptor) is about 20 or less.

10. The peptide variant of claim 2, wherein the (EC50) at the glucagon receptor)/(EC50 at the GLP-1 receptor) is about 20 or less.

11. A conjugate comprising a variant peptide of claim 2 conjugated to a heterologous moiety.

12. The conjugate of claim 11, wherein the heterologous moiety comprises one or more of:

a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment thereof, a polymer, a quantum dot, a small molecule, a toxin, a diagnostic agent.

13. The conjugate of claim 11, comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 29 or the variant peptide.

14. The conjugate of claim 13, wherein the extension is selected from the group consisting of:

Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO;

     9) or GGPSSGAPPPS (SEQ ID NO;

     10).

15. A dimer or multimer comprising a variant peptide of claim 2.

16. A pharmaceutical composition comprising the variant peptide of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method of treating a disease or medical condition in a patient in need of treatment, wherein the disease or medical condition is selected from the group consisting of:

metabolic syndrome, diabetes, obesity and liver steatosis, comprising administering to the patient the pharmaceutical composition of claim 16 in an amount effective to treat the disease or medical condition.

18. A conjugate comprising the peptide of claim 1 conjugated to a heterologous moiety.

19. The conjugate of claim 18, wherein the heterologous moiety comprises one or more of:

a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment therefore, a polymer, a quantum dot, a small molecule, a toxin, or a diagnostic agent.

20. The conjugate of claim 19, comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 29 of the peptide.

21. The conjugate of claim 20, wherein the extension is selected from the group consisting of:

Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO;

     9) or GGPSSGAPPPS (SEQ ID NO;

     10).

22. A dimer or multimer comprising the peptide of claim 1.

23. A pharmaceutical composition comprising the peptide of claim 1, or a pharmaceutically acceptable salt;

and a pharmaceutically acceptable carrier.

24. A method of treating a disease or medical condition in a patient in need of treatment, wherein the disease or medical condition is selected from the group consisting of:

metabolic syndrome, diabetes, obesity and liver steatosis, comprising administering to the patient the pharmaceutical composition of claim 23 in an amount effective to treat the disease or medical condition.