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Insulin derivatives containing additional disulfide bonds

A technology of insulin derivatives and insulin, applied in the field of insulin derivatives and their preparation, can solve the problem of no insulin disulfide bond, etc., to achieve improved chemical stability, improved chemical and/or physical stability, improved chemical and/or or the effect of physical stability

Inactive Publication Date: 2016-10-26
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, no engineered disulfide bonds in insulin have been reported

Method used

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  • Insulin derivatives containing additional disulfide bonds
  • Insulin derivatives containing additional disulfide bonds
  • Insulin derivatives containing additional disulfide bonds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0428] Embodiment 1, general method (A):

[0429] A10C, A14E, B4C, B25H, B29K (N ε octadecanedioyl-gGlu-OEG-OEG), desB30 human insulin

[0430] IUPAC (OpenEye, IUPAC type) name:

[0431] N{ε-B29}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyryl] amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[CysA10, GluA14, CysB4, HisB25], des-ThrB30-insulin (human)

[0432] Dissolve A10C, B4C, A14E, B25H, desB30 human insulin (2 g) in 100 mM Na 2 CO 3 aqueous solution (50 mL), and NMP (3 mL) was added. The pH was adjusted to 11.2 with 1N NaOH. Octadecandioyl-gGlu-OEG-OEG-OSu (0.8 g, 1.4 equiv.) dissolved in NMP (6 mL) was added while maintaining the pH at about 11 with 1 N NaOH. After 5 minutes, water (40 mL ), the pH was lowered to 5.5 by adding 1N HCl. The precipitate was isolated by centrifugation. The residue was dissolved in acetonitrile (30 mL) and water (30 mL) containing 1% TFA and purified by 4 runs of HPLC:

[0433] Column: Phenomenex, G...

Embodiment 2

[0446] Embodiment 2, general method (A):

[0447] A10C, A14E, B3C, B25H, B29K (N(ε) octadecanedioyl-gGlu), desB30 human insulin

[0448] IUPAC (OpenEye, IUPAC type) name:

[0449] N{ε-B29}-[(4S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyryl]-[CysA10, GluA14, CysB3, HisB25], des-ThrB30-insulin (human)

[0450] LCMS (electrospray): m / z = 1517.0 (M+4) / 4 (6064).

Embodiment 3

[0451] Embodiment 3, general method (A):

[0452] A10C, A14E, B3C, B25H, B29K (N ε octadecanedioyl), desB30 human insulin

[0453] IUPAC (OpenEye, IUPAC type) name:

[0454] N{ε-B29}-17-Carboxyheptadecanoyl-[CysA10, CysB3, HisB25], des-ThrB30-Insulin (Human)

[0455] MS (electrospray) m / 4: m / z = 1485.0 (5935.9). Calcd.: 1484.8.

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Abstract

The present invention relates to insulin derivatives comprising additional disulfide bonds and processes for their preparation.

Description

field of invention [0001] The present invention relates to insulin derivatives comprising additional disulfide bonds and processes for their preparation. Background of the invention [0002] Diabetes mellitus is a metabolic disease in which the ability to utilize glucose is partially or completely lost. In the treatment of diabetes, many kinds of insulin preparations have been proposed and used, such as regular insulin, low protamine zinc insulin (designated as NPH), insulin zinc suspension (such as Semilente 、Lente and Ultralente ) and biphasic protamine zinc insulin. [0003] Human insulin consists of two polypeptide chains, the A and B chains, which contain 21 and 30 amino acid residues, respectively. The A and B chains are connected to each other by two disulfide bonds. Insulins from most other species are similar but may contain amino acid substitutions at some positions. During the past decade, many analogs of human insulin have been developed. They are desig...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/62
CPCC07K14/62A61P3/10A61K38/28
Inventor P·马德森F·胡巴莱克T·B·克杰尔德森S·卢德维格森
Owner NOVO NORDISK AS