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A polyethylene glycol conjugate of teduglutide and its solid-phase preparation method

A technology of solid-phase preparation and polyethylene glycol, which is applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problems of wide Mr distribution of protein molecules, immunogenicity, short half-life, etc.

Active Publication Date: 2017-02-08
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, short half-life, immunogenicity, easy to be degraded by proteolytic enzymes, poor solubility, etc.
Traditional PEG modification is mostly random modification, and there are outstanding problems such as modifiers showing various degrees of polymerization, insufficient selectivity, wide Mr distribution of modified protein molecules, reduced activity, and sometimes unsatisfactory stability.

Method used

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  • A polyethylene glycol conjugate of teduglutide and its solid-phase preparation method
  • A polyethylene glycol conjugate of teduglutide and its solid-phase preparation method
  • A polyethylene glycol conjugate of teduglutide and its solid-phase preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the synthesis of the Fmoc-Asp(OtBu)-Wang resin that substitution degree is 0.1mmol / g

[0041] Weigh 40 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 4.94g Fmoc-Asp(OtBu)-OH (12mmol), 1.95g HOBt (14.4mmol) and 0.15g DMAP (1.2mmol) and dissolve in the mixed solution of DCM and DMF with a volume ratio of 1:1, add 2.25ml of DIC (14.4mmol) was activated for 3 minutes and then added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 70ml of blocking solution (pyridine / acetic anhydride = 1:1, 400mmol: 400mmol) to block for 8 hours (if the resin is not fully diffused, add DCM as a solvent). Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-Wang resin. The detected substitution degree was 0.098mmol / g.

Embodiment 2

[0042] Embodiment 2: the degree of substitution is the synthesis of Fmoc-Asp(OtBu)-Wang resin of 0.19mmol / g

[0043] Weigh 40 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 9.38g Fmoc-Asp(OtBu)-OH (22.8mmol), 3.70g HOBt (27.4mmol) and 0.28g DMAP (0.23mmol) and dissolve them in a mixed solution of DCM and DMF with a volume ratio of 1:1. Add 4.28ml DIC (27.4mmol) to activate for 3 minutes, then add to the solid phase reaction column, and react at room temperature for 2 hours. Wash 3 times with DMF, add 70ml of blocking solution (pyridine / acetic anhydride = 1:1, 400mmol: 400mmol) to block for 8 hours (if the resin is not fully diffused, add DCM as a solvent). Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-Wang resin. The detected substitution degree was 0.192mmol / g.

Embodiment 3

[0044] Embodiment 3: the degree of substitution is the synthesis of Fmoc-Asp(OtBu)-Wang resin of 0.15mmol / g

[0045] Weigh 40 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 7.42g Fmoc-Asp(OtBu)-OH (18mmol), 2.92g HOBt (21.6mmol) and 0.22g DMAP (1.8mmol) and dissolve in the mixed solution of DCM and DMF with a volume ratio of 1:1, add 3.38ml DIC (21.6mmol) was activated for 3 minutes and then added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 70ml of blocking solution (pyridine / acetic anhydride = 1:1, 400mmol: 400mmol) to block for 8 hours (if the resin is not fully diffused, add DCM as a solvent). Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-Wang resin. The detection substitution degree was 0.150mmol / g.

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Abstract

The invention relates to the field of polypeptide synthesis, and particularly relates to a teduglutide polyethylene glycol conjugate and a solid-phase preparation method thereof. By the solid-phase synthesis method, teduglutide is modified by PEG with fixed sites, thus changing properties of the teduglutide. The conjugate and the method are mainly advantaged by prolonging the half-life period of proteins (polypeptides) in vivo and reducing immunogenicity and antigenicity.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a polyethylene glycol conjugate of teduglutide and a solid-phase preparation method thereof. Background technique [0002] Short bowel syndrome (SBS) refers to a series of syndromes caused by the body's inability to absorb nutrients normally due to severe small bowel disease or surgical removal of a large part of the small intestine. SBS reduces patients' ability to take in fluids and nutrients, causing them to become dehydrated and malnourished. Parenteral nutrition support will increase the risk of systemic infection and other long-term complications. So far, there is no drug to treat short bowel syndrome. [0003] Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is a naturally occurring hormone that reduces gastric emptying and secretion, and regulates the growth, Proliferation and repair. Teduglutide was designated as an orphan drug in 2001. Clinical trials have...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C07K1/113C07K1/06C07K1/04
CPCY02P20/55
Inventor 宓鹏程刘建潘俊锋马亚平袁建成
Owner HYBIO PHARMA