GIP receptor-active glucagon compounds

• US 9,790,263 B2
• Filed: 08/31/2015
• Issued: 10/17/2017
• Est. Priority Date: 06/16/2009
• 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., Ma, Tao
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): Deberry, Regina M
• Application Number:
  US14/840,580
• Publication Number:
  US 20160052989A1
• Time in Patent Office: 778 Days
• Field of Search: None
• 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 38/26 Glucagons
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Glucagon peptides with increased GIP activity are provided, optionally with GLP-1 and/or glucagon activity. In some embodiments, C-terminally extended glucagon peptides comprising an amino acid sequence substantially similar to native glucagon are provided herein.

Claims

1. A method of reducing weight gain or inducing weight loss in a patient, said method comprising administering to said patient an effective amount of a peptide comprising (A) the amino acid sequence of SEQ ID NO:

1 with the following amino acid modifications and (B) the amino acid sequence of GPSSGAPPPS (SEQ ID NO;

     26) C-terminal to the amino acid at position 29 of SEQ ID NO;

1,

wherein the amino acid at position 2 is selected from the group consisting of;

D-serine, alanine, D-alanine, valine, glycine, N-methyl serine, N-methyl alanine, and amino isobutyric acid (AIB),

wherein the amino acid at position 16 is Glu, the amino acid at position 17 is Gln, the amino acid at position 18 is Ala, the amino acid at position 20 is Lys, the amino acid at position 21 is Glu, the amino acid at position 23 is Be, the amino acid at position 24 is Ala, and the amino acid at position 29 is a small aliphatic amino acid,

wherein;

(a) the peptide further comprises at position 40 an amino acid comprising an acyl or alkyl group, which is non-native to a naturally-occurring amino acid, or

(b) the peptide comprises an amino acid comprising an acyl or alkyl group, which is non-native to a naturally-occurring amino acid, at position 10 of the peptide, or

(c) a combination of (a) and (b);

wherein, when the peptide lacks a hydrophilic moiety, the peptide exhibits at least 10% activity of native GIP at the GIP receptor, wherein the GIP potency of the peptide is within about 100-fold of GLP-1 potency of the peptide.

2. The method of claim 1, wherein said peptide comprises a C-terminal amide.

3. The method of claim 1, wherein the amino acid at position 29 of said peptide is Gly.

4. The method of claim 1, wherein the amino acid of said peptide comprising an acyl or alkyl group is an amino acid of Formula I:

5. The method of claim 4, wherein the amino acid comprising an acyl or alkyl group is Lys.

6. The method of claim 1, wherein the amino acid comprising an acyl or alkyl group is located at position 40 of the peptide.

7. The method of claim 1, wherein the acyl group is a C4 to C30 fatty acyl group.

8. The method of claim 7, wherein the acyl group is a C12 to C18 fatty acyl group.

9. The method of claim 1, wherein the acyl or alkyl group is covalently attached to the side chain of the amino acid via a spacer.

10. The method of claim 9, wherein the spacer is an amino acid or dipeptide.

11. The method of claim 1, wherein the GIP potency of the analog is within about 500-fold of the glucagon potency of the peptide.

12. A method of reducing weight gain or inducing weight loss in a patient, said method comprising administering to said patient an effective amount of a peptide comprising (A) the amino acid sequence of SEQ ID NO:

1 with the following amino acid modifications and (B) the amino acid sequence of GPSSGAPPPS (SEQ ID NO;

     26) C-terminal to the amino acid at position 29 of SEQ ID NO;

1, wherein

the amino acid at position 2 is amino isobutyric acid (AIB);

the amino acid at position 16 is Glu;

the amino acid at position 17 is Gln;

the amino acid at position 18 is Ala;

the amino acid at position 20 is Lys;

the amino acid at position 21 is Glu;

the amino acid at position 23 is Ile;

the amino acid at position 24 is Ala;

the amino acid at position 29 is Gly;

wherein said peptide further comprises an acylated Lys at position 40 and a C-terminal amide,

wherein said acylated Lys comprises a C4 to C30 fatty acyl group.

13. The method of claim 12 wherein said peptide comprises the sequence of His-AIB-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Met-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys (SEQ ID NO:

669), wherein the Lys at position 40 is acylated with a C16 fatty acid.