Glucagon-like peptide-2 (GLP-2) analog, and preparation method and use thereof

A technology of GLP-2 and analogues, which is applied in the field of analogues of glucagon-like peptide-2 (GLP-2) and its preparation and application, and can solve the problem of limiting the use of GLP-2 and the low stability of endogenous DPPIV To achieve the effect of improving tolerance, improving chemical stability, and reducing the possibility of being degraded

Active Publication Date: 2013-02-13
CHINESE PEPTIDE CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although the intestinal specificity of GLP-2 and its beneficial pharmacological effects have attracted people's attention, the low stability of GLP-2 relative to endogenous DPPIV greatly limits the use of GLP-2

Method used

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  • Glucagon-like peptide-2 (GLP-2) analog, and preparation method and use thereof
  • Glucagon-like peptide-2 (GLP-2) analog, and preparation method and use thereof
  • Glucagon-like peptide-2 (GLP-2) analog, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of Example 1 GLP-2 Analogs

[0041] According to the conventional method of solid-phase synthesis, the amino acids with protective groups are attached to the resin one by one, and then the catalyst is used to catalyze the ring closure, and then the protective group is removed and the polypeptide is cut off from the resin to prepare the preferred GLP-2 similar to the following formula: thing:

[0042]

[0043] 1. Solid phase synthesis

[0044] Select 0.45g Fmoc-Asp(OtBu)-Wang resin (substitution degree: 0.33mmol / g) to prepare, soak the resin with DMF at room temperature for 60min, and arrange the amino acids with Fmoc protection in the synthesizer in order for activation connection , get as figure 1 The product of compound 2 in, the structure is:

[0045]

[0046] 2. Catalytic cyclization

[0047] The compound obtained in the above steps was washed twice with DCM (20ml) and DCE (20ml) respectively, then soaked with DCE (8ml) for 30min, and then Grubbs...

Embodiment 2

[0052] Example 2 Determination of resistance to dipeptidyl peptidase IV (DPP-IV)

[0053] To detect the DPP-IV resistance of rGLP-2 and the GLP-2 analog of Example 1, 2.5 μl of recombinant human DPP-IV (purchased from ProSpec) containing 0.125 mU was dissolved in 20 mM Tris-HCl buffer (pH 8) , 100mM NaCl, 1mM EDTA, 10% glycerin solution, add 50ul PBS solution (pH7.4) containing 0.2mg / ml peptide to be tested. Incubate in a circulating water bath at 37° C. for 24 hours, and add 50 ul of a PBS solution containing 4 mg / ml diprotinA (purchased from BIOPRC) to quench the incubation. Each sample was analyzed by reversed-phase (PR) HPLC: 90 ul of the quenched incubation mixture was injected into a Dynamax (available from Rainin) 300A, C5 (5 micron, 4.6*250 mm) column, and the sample was washed with acetonitrile containing 0.1% TFA Elution was performed with a linear gradient of modified water at a flow rate of 1 ml / min, the sample components were detected at 214 nm, and the degree of...

Embodiment 3

[0054] Example 3 Pharmacodynamic evaluation of GLP-2 analogues

[0055] Select normal male SD rats (200+-20g), and randomly divide them into 3 groups, 6 rats / group, respectively PBS control group, rGLP-2 group, and Example 1 GLP-2 analog group. According to the administration of 0.5mg / kg / day, the abdomen was subcutaneously injected for 10 days, then sacrificed, the small intestine was taken, washed with normal saline, and weighed. like figure 2 The results showed that, compared with the PBS group, both the rGLP-2 group and the GLP-2 analogue group of Example 1 could significantly promote intestinal growth.

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Abstract

The invention relates to a new GLP-2 analog and a preparation method thereof. Compared with natural GLP-2, the GLP-2 analog has the advantages of improved chemical stability, and reservation of the pharmacological activities of the natural GLP-2. The GLP-2 analog has a chemical structure represented by a formula shown in the specification.

Description

technical field [0001] The present invention relates to analogues of glucagon-like peptide-2 (GLP-2) and methods for their preparation and use in the prevention and treatment of, for example, gastrointestinal-related disorders and the alleviation of side effects of chemotherapy and radiotherapy. Background technique [0002] GLP-2 belongs to the proglucagon-derived peptide (PGDP), which is one of the degradation products of proglucagon (PG) by prohormone convertase (PC). Intestinal L endocrine cells synthesize and release, and are regulated by factors such as feeding, nerve and endocrine. [0003] GLP-2 can specifically stimulate the growth of intestinal mucosa, enhance the regeneration of intestinal mucosa after injury; inhibit the apoptosis of intestinal mucosal epithelial cells and crypt cells; enhance the transport of glucose and glucose transporter-2 on the basal side of intestinal epithelial cells (glucosetransporter-2, GLUT2) expression, promote intestinal digestion ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04A61K38/26A61P1/00
Inventor 李湘
Owner CHINESE PEPTIDE CO
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