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Polyethelene glycol link glp-1 compounds

一种GLP-1、化合物的技术，应用在疾病或病症的相关组合物领域，能够解决分子不适用治疗、分子不稳定性和生物活性降低等问题

Inactive Publication Date: 2006-09-13
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Covalent attachment of one or more molecules of polyethylene glycol to small biologically active peptides such as GLP-1 or exendin-4 risks introducing unfavorable properties, such as instability and reduced biological activity of the molecule, which This risk can be severe enough to make the molecule unsuitable for therapeutic use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] Example 1 - PEGylation of GLP-1 related analogs:

[0334] The PEGylation reaction is performed under conditions that allow the formation of thioether linkages. Specifically, the pH of the solution ranges from about 4-9 and the concentration of the thiol-containing peptide ranges from 1-10 molar over the concentration of methoxy PEG2-MAL. Normal PEGylation reactions were performed at room temperature. The PEGylated GLP-1 peptides were then isolated using reverse phase HPLC or size exclusion chromatography (SEC). PEGylated GLP-1 analogs were characterized using analytical RP-HPLC, HPLC-SEC, SDS-PAGE and / or MALDI mass spectrometry.

[0335] To generate derivatives covalently linked to PEG via thioether linkages, thiol-containing GLP-1 peptides were reacted with 40 kDa polyethylene glycol-maleimide (PEG-maleimide). For example, the peptide Cex-51-C (V 8 E. 22 I 33 C 40 GLP-1, 45 aa in length, 7.5 mg, 1.8 μmol) was dissolved in 2 ml of 200 mM phosphate buffer pH 7.4 ...

Embodiment 2-40

[0336] Embodiment 2-40kDa-PEG-maleimide reacts with GLP analogs

[0337] GLP-1 analogs such as C 16 E. 22 V 8 GLP and V 8 C 38 GLP is selectively PEGylated on the introduced cysteine ​​residues. For the PEGylation reaction, the peptide to be PEGylated was dissolved in 100 mM TRIS buffer pH 8.0 and the peptide was added at a 1.25-fold molar concentration over 40 kDa-mPEG. Reactions were stirred at room temperature for 2-3 hours and then dialyzed (7 kDa membrane) overnight at approximately 5°C against 10 mM citrate, 10 mM phosphate, pH 7.4. PEGylated GLP molecules were purified by anion exchange chromatography using a neutral pH NaCl gradient on a Mono-Q column (Amersham Biosciences Corp, Piscataway, NJ).

Embodiment 3-D

[0338] Embodiment 3-DSPE-3.4kDa-PEG-maleimide reacts with GLP-1 analog

[0339] GLP-1 analogs such as C 16 E. 22 V 8 GLP-1 and V 8 C 38 GLP-1 is selectively PEGylated on the introduced cysteine ​​residues. For the PEGylation reaction, the peptide was dissolved in 100 mM TRIS buffer pH 8.0 and the peptide was added at a 1.25-fold molar concentration over DSPE-3.4 kDa-PEG maleimide. Absolute ethanol was added to approximately 17% to aid dissolution of DSPE-3.4kDa-PEG-maleimide. Reactions were stirred at room temperature for 2-3 hours and then dialyzed (7 kDa membrane) overnight at approximately 5°C against 10 mM citrate, 10 mM phosphate, pH 7.4. PEGylated GLP molecules were purified by anion exchange chromatography using a neutral pH NaCl gradient on a Mono-Q column (Amersham Biosciences Corp, Piscataway, NJ).

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PUM

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Abstract

The invention provides GLP-1 compounds coupled to at least one polyethylene glycol molecule or derivative thereof, resulting in a biologically active peptide with an extended half-life and a slower clearance when compared to that of unPEGylated peptide. These PEGylated GLP-1 compounds and compositions are useful in treating diabetes, obesity, irritable bowel syndrome and other conditions that would be benefited by lowering plasma glucose, inhibiting gastric and / or intestinal motility and inhibiting gastric and / or intestinal emptying, or inhibiting food intake.

Description

field of invention [0001] The present invention relates to GLP-1 compounds or derivatives thereof to which one or more polyethylene glycol molecules are covalently linked, and to related compositions and methods useful in the treatment of diseases or disorders wherein the diseases or disorders can be Benefit by lowering blood sugar, reducing food absorption, reducing gastrointestinal emptying, or reducing gastrointestinal motility. Background of the invention [0002] Glucagon-like peptide-1 (GLP-1) causes various biological effects, such as stimulation of insulin secretion, inhibition of glucagon secretion, inhibition of gastric emptying, inhibition of gastric motility or intestinal motility, enhancement of Glucose utilization and weight loss. GLP-1 can further prevent pancreatic β-cell degeneration that occurs as a progression of non-insulin-dependent diabetes mellitus (NIDDM). A distinctive feature of GLP-1 is its ability to stimulate insulin secretion without the risks...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00A61K38/26A61K38/00A61KA61K6/00A61K31/205A61K47/10A61K47/48A61P1/00A61P3/04A61P3/10C07K14/605C07K17/08
CPCA61K47/48215C07K14/605A61K47/60A61P1/00A61P1/04A61P1/14A61P3/04A61P3/10A61P9/00A61P9/10A61K31/205C07K14/00
Inventor R·D·迪马其W·格莱斯纳R·L·小米利肯A·M·维克张连山
Owner ELI LILLY & CO
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