Insulin analogs

Patent metadata

Field	Value
Publication number	US-11248034-B2
Application number	US-201716319450-A
Country	US
Kind code	B2
Filing date	Jul 21, 2017
Priority date	Jul 22, 2016
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

The present invention relates to insulin analogs, particularly insulin analogs having shortened B chains. The present invention also relates to the crystal structure of insulin from the venom of cone snails and to methods of using the crystal and related structural information to screen for and design insulin analogs that interact with or modulate the insulin receptor. The present invention also relates to therapeutic and prophylactic methods using insulin analogs.

First claim

The invention claimed is:

1. A peptide comprising an A chain and a B chain, wherein the A chain comprises a sequence set forth in SEQ ID NO:1, wherein the B chain comprises a sequence set forth in SEQ ID NO:30, and wherein:
X A2 =Ile; X A3 =Val; X A4 =Glu; X A5 =Gln; X A6 =Cys, X A7 =Cys; X A8 =His; X A9 =Arg; X A10 =Ile; X A11 =Cys; X A12 =Ser; X A13 =Leu; X A14 =Tyr; X A15 =Gln; X A16 =Leu; X A17 =Glu; X A18 =Asn; X A19 =Tyr; X A20 =Cys, X A21 =Asn, Pro, His, Ser, Gly, Ala, or is absent; and X A22 to X A34 =absent.

2. The peptide of claim 1 , wherein the A chain has the sequence GIVEQCCHRICSLYQLENYCG (SEQ ID NO:58).

3. The peptide of claim 1 , wherein the A chain has the sequence GIVEQCCHRICSLYQLENYCG (SEQ ID NO:58) and the B chain has the sequence FVNQHLCGSELVEALYLVCYER (SEQ ID NO:30).

4. The peptide of claim 3 , wherein the A chain and B chain are bonded via at least one disulfide bond.

5. The peptide of claim 4 , wherein the A chain and B chain are bonded via at least 2 disulfide bonds.

6. The peptide of claim 5 , wherein the A chain and B chain are bonded via at least 3 disulfide bonds.

7. The peptide of claim 6 , wherein the at least 2 disulfide bonds are between the first Cys and the third Cys in the A chain, or between the second Cys in the A chain and the first Cys in the B chain, or between the fourth Cys in the A chain and the second Cys in the B chain.

8. The peptide of claim 7 , wherein there are disulfide bonds between the first Cys and the third Cys in the A chain, between the second Cys in the A chain and the first Cys in the B chain, and between the fourth Cys in the A chain and the second Cys in the B chain.

9. The peptide of claim 8 , wherein the peptide is a monomer.

10. The peptide of claim 1 , wherein the peptide is a des-octapeptide insulin.

11. The peptide of claim 1 , wherein:
(a) the insulin analog has an IC 50 against the human IR-B receptor of less than 10 −6 M; and/or
(b) at least 75% of the analog is monomeric in solution; and/or
(c) the peptide has increased bioavailability when administered to a human when compared to human insulin; and/or
(d) the peptide has a peak bioavailability within 0.5 to 3 hours of administration to a human; and/or
(e) the peptide has an onset of activity within 10 minutes of administration; and/or
(f) the peptide does not bind human IGF-IR or binds human IGF-IR weakly; and/or
(g) the peptide has an affinity (Kct) for human IGF-IR of weaker than 100 nM.

12. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.

13. A method of increasing insulin receptor activation in a subject comprising administering a therapeutically effective amount of the peptide of claim 1 to a subject in need thereof.

14. A method of lowering the blood sugar in a subject comprising administering a therapeutically effective amount of the peptide of claim 1 to a subject in need thereof.

15. The method of claim 14 , wherein the subject has been diagnosed with type 1 diabetes prior to administering the peptide.

16. A method of treating type 1 diabetes in a subject comprising administering a therapeutically effective amount of the peptide of claim 1 to a subject in need thereof.

Assignees

• Univ Utah Res Found
• Walter & Eliza Hall Inst Medical Res

Inventors

• Menting John Gerbrandt Tasman
• Smith Brian
• Chou Danny Hung-Chieh
• Safavi-Hemami Helena
• Lawrence Michael Colin
• Olivera Baldomero M

Classifications

• A61K38/00 Primary

  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 title

• G16B15/30

  Drug targeting using structural data; Docking or binding prediction · CPC title

• C07K2299/00

  Coordinates from 3D structures of peptides, e.g. proteins or enzymes · CPC title

• C07K14/62 Primary

  Insulins · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title