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Glucagon-like peptide-2 analogue and its preparation method and application

An analogue, GLP-2 technology, applied in the direction of glucagon, peptide preparation methods, hormone peptides, etc., can solve the problem of short half-life

Active Publication Date: 2016-08-10
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, many studies have adopted GLP-2 analog fusion protein technology to solve the retention time of GLP-2 analogs in the body (CN200680015213.5; CN200380101375.7; CN200680047664.7; CN200780041490.8; CN200510039265.3; CN200910126363.9 ), however, most of them change the structure of GLP-2 through mutations of amino acid residues such as substitution and deletion, which can resist the degradation of DPP-IV to a certain extent, but there is still a long way to go from the ideal clinical goal
[0007] Therefore, there is currently a need for methods to address the short in vivo half-life of GLP-2

Method used

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  • Glucagon-like peptide-2 analogue and its preparation method and application
  • Glucagon-like peptide-2 analogue and its preparation method and application
  • Glucagon-like peptide-2 analogue and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the solid-phase synthesis of polypeptide

[0075] This example takes SEQ ID NO: 6 as an example, using the solid-phase peptide synthesis method of the Fmoc strategy, using the CS336X instrument produced by CS Bio to synthesize the polypeptide of the present invention, and the synthesis method is carried out according to the manufacturer's instrument instructions.

[0076] The prepared polypeptide was purified using an HPLC C18 semi-preparative column (purchased from Phenomenex), and the mobile phase was acetonitrile. The polypeptide freeze-dried powder is obtained by desalting and freeze-drying. The polypeptides included in this patent all contain disulfide bonds, and ammonium bicarbonate or other reducing agents are used to form disulfide bonds in the polypeptides. This example specifically takes dimethyl sulfoxide as an example to form a disulfide bond. First, dissolve the polypeptide with 5% acetic acid, adjust the concentration of the polypeptide to...

Embodiment 2

[0079] Embodiment 2: Determination of serum half-life of GLP-2 analog (general formula II)

[0080] In this embodiment, the polypeptides used are as follows:

[0081] SEQ ID NO:2: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGCGGG;

[0082] SEQ ID NO:3: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGCGGG;

[0083] SEQ ID NO:4: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGGGGGGCGGG;

[0084] SEQ ID NO:5: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGCGGGGGG;

[0085] SEQ ID NO:6: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGCGGGGGGGGG;

[0086] SEQ ID NO:7: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGCGGGGGG;

[0087] SEQ ID NO:8: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGCGGGGGGGGG;

[0088] SEQ ID NO:9: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGGGGGGCGGGGGG;

[0089] SEQ ID NO:10: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 GGGGGGGGGGGGGGGCGGGGGGGGG;

[0090] SEQ ID NO: 11: 1 HADGSFSCEMNTILDNLAARDFINWLIQTKITD 33 AAAAACAAA;

[0091]...

Embodiment 3

[0113] Embodiment 3: Determination of serum half-life of GLP-2 analog (general formula III)

[0114] In this embodiment, the polypeptides used are as follows:

[0115] SEQ ID NO:29: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GCGGGGGGGGGG;

[0116] SEQ ID NO: 30: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GCGGGGGGGGGGGGGGG;

[0117] SEQ ID NO: 31: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GCGGGGGGGGGGGGGGGGGGGGGGGGG;

[0118] SEQ ID NO: 32: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGCGGGGGGGGGG;

[0119] SEQ ID NO: 33: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGCGGGGGGGGGGGGGGG;

[0120] SEQ ID NO: 34: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGCGGGGGGGGGGGGGGGGGGGG;

[0121] SEQ ID NO: 35: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGGGGCGGGGGGGGGG;

[0122] SEQ ID NO: 36: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGGGGCGGGGGGGGGGGGGGG;

[0123] SEQ ID NO: 37: 1 HADGSFSDEMNTILDNLAARDFICWLIQTKITD 33 GGGGGCGGGGGGGGGGGGGGGGGGGG;

[0124] SEQ ID NO: 38: 1 HADGSFSDEMNTILDNLAARD...

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Abstract

The invention provides a glucagon-like peptide-2 (GLP-2) analog, and a preparation method and an application thereof. The sequence of the GLP-2 analog is <1>HADX4SFSX8EMNTILDX16LAARDFIX24WLX27QTKITD<33>n1X1C n2X2 represented by SEQ ID NO:1, wherein X4 is glycine or cysteine; X8 is aspartic acid or cysteine; X16 is asparagine or cysteine; X24 is aspartic acid or cysteine; X27 is isoleucine or cysteine, only one of X4, X8, X16, X24 and X27 is cysteine, and cysteine is bonded with another cysteine through a disulfide bond; n1X1 represents n1 X1, and n1 is 1-30; and n2X2 represents n2 X2, and n2 is 0-30. The GLP-2 analog overcomes the short half life problem of GLP-2.

Description

technical field [0001] The present invention relates to a glucagon-like peptide-2 (Glucagon-like peptide-2) analogue and its preparation method and application, specifically, using the modified glucagon-like peptide-2 analogue in The medical application of prevention or treatment of gastrointestinal related diseases, restoration of intestinal mucosal injury, promotion of small intestine growth, promotion of absorption function of transplanted small intestine and restoration of ultrastructure belongs to the field of biomedicine technology. Background technique [0002] The glucagon-like peptide-2 (glucagon-like peptide-2, hereinafter referred to as: GLP-2) involved in the present invention is a single-chain polypeptide composed of 33 amino acid residues ( 1 HADGSF SDEMNTILDNLAARDFINWLIQTKITD 33 ), mainly secreted by intestinal specific tissues and L cells, encoded and expressed by proglucagon gene, highly expressed in pancreas, intestinal tract and brain tissue, and is degra...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61P1/00A61P1/04C07K1/04
CPCA61K38/00C07K14/605
Inventor 王玉丽徐为人汤立达邹美香吴疆白玫郑学敏龚珉
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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