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Oral hypoglycemic polypeptide, fatty acid modified derivative and application thereof

A technology for lowering blood sugar and fatty acids, applied in the field of medicine and biology, can solve the problems of low oral availability, large molecular weight, poor fat solubility, etc., and achieve the effect of avoiding the failure of enzymatic hydrolysis

Inactive Publication Date: 2019-03-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low oral availability of biotechnological drugs, no practical results have been obtained. At present, there are still no related biotechnological drugs that can be administered orally. The main reasons are two aspects: 1. Biotechnological drugs are mostly peptides , protein and other biomacromolecules, which have large molecular weight and poor fat solubility, are difficult to absorb in the intestine; 2. There are a large number of proteases in the intestine, which will quickly degrade the biomacromolecules entering the intestine, so that the drugs in the intestine cannot be maintained. Concentration required for treatment

Method used

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  • Oral hypoglycemic polypeptide, fatty acid modified derivative and application thereof
  • Oral hypoglycemic polypeptide, fatty acid modified derivative and application thereof
  • Oral hypoglycemic polypeptide, fatty acid modified derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Determination of IPCM1-8 resistance to enzymatic hydrolysis

[0061] Use high-performance liquid chromatography to measure the anti-enzymolysis ability of IPCM1-8:

[0062] Step 1: Prepare three 0.005 mg / mL protease solutions, the three proteases are trypsin, chymotrypsin, and elastase, and incubate each protease solution at 37°C for 15 minutes.

[0063] Step 2: Mix 500 μL of 0.5 mg / mL IPCM1-8 solution with 500 μL of each protease solution, that is, each protease: IPCM1-8=1:100 (w / w), react at 37°C, and then At each predetermined time point (0, 5, 15, 30, 60 min), 50 μL of the reaction solution was taken out, and 50 μL of 1% TFA solution was added to terminate the reaction. After centrifugation at 12000 rpm for 5 min, the supernatant was collected and detected by RP-HPLC. At the same time, Exendin-4C (i.e. exenatide) was used as a control sample, which was treated and detected with the same volume and concentration.

[0064] The third step: use RP-HPLC dete...

Embodiment 2

[0070] Example 2 Determination of the ability of IPCM1-8 to activate the glucagon-like peptide-1 receptor

[0071] Step 1: After recovering the CHO / GLP-1R-CRE chemiluminescent cell line, transfer it to a culture flask containing 5 mL of cell growth medium, and store it at 37°C, 5% CO 2 cultured in an incubator. When the cells grew to about 80% of the adherent surface of the cells, they were digested with 0.25% trypsin and passaged at a ratio of 1:3 every 3 days. After passage to the third passage, the in vitro activity assay was performed using the luciferase reporter gene method.

[0072] Step 2: During the experimental determination, the cells were first digested with 0.25% trypsin, and then the assay medium was added. Take 2×10 5 The amount of cells / mL was inoculated into a 96-well plate with 100 μL per well, at 37°C, 5% CO 2 Incubate for 4 h in the incubator.

[0073] Step 3: Take out the 96-well plate and add 20 μL of IPCM1-8 solution / Exendin-4 positive control to ea...

Embodiment 3

[0081] Example 3 Anti-enzymolysis ability and ability to activate glucagon-like peptide-1 receptor of other sequences except IPCM1-8

[0082] Except for IPCM1-8, the amino acids at each position of the other sequences included in the general formula of the polypeptide of the present invention are shown in the following table:

[0083]

[0084]

[0085]

[0086]

[0087] The above sequence was measured according to the method of Example 1, except that in the second step, 50 μL of the reaction solution was taken out at 60 minutes after mixing with the protease.

[0088] The above sequence was used to determine the ability to activate glucagon-like peptide-1 receptor according to the method in Example 2.

[0089] Due to the limited space, the specific experimental data will not be listed here one by one. The results showed that compared with Exendin-4C, the resistance of IPCM9-96 to the three proteases was improved to varying degrees; at the same time, IPCM9-96 had t...

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Abstract

The invention relates to oral hypoglycemic polypeptide, a fatty acid modified derivative and an application thereof. The sequence of the polypeptide is shown in SEQ ID NO.1. The modification site of the fatty acid modified derivative is one of Xaa1, Xaa2, Xaa4 or any combination thereof. The polypeptide and the fatty acid modified derivative thereof can be used for preparing drugs or drug compositions for preventing or treating diabetes, or for preparing hypoglycemic drugs or drug compositions. Compared with the prior art, the polypeptide and the fatty acid modified derivative thereof have enzymolysis resistance to multiple proteases, and can better avoid enzymolysis failure in gastrointestinal tract, so that the polypeptide and the fatty acid modified derivative thereof are more suitableto be used as oral hypoglycemic drugs.

Description

technical field [0001] The present invention relates to an oral hypoglycemic polypeptide, a fatty acid modified derivative of the polypeptide, and their uses; the polypeptide and its fatty acid modified derivative have resistance to enzymatic hydrolysis by major intestinal proteases, and at the same time have good intestinal permeability property; belongs to the field of medical biotechnology. Background technique [0002] Diabetes is a lifelong metabolic disease characterized by persistent hyperglycemia caused by multiple etiologies. Its complications involve cardiovascular and cerebrovascular tissues, kidney tissues, eyes, feet and other tissues and organs. , it is difficult to reverse. Pathologically, diabetes can be divided into two types: type I diabetes, which manifests as decreased or complete loss of insulin secretion, and type II diabetes, which manifests as the inability of the body to effectively use insulin. Among them, type II diabetes accounts for 90% of the ...

Claims

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Application Information

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IPC IPC(8): C07K14/575A61K38/22A61P3/10
CPCA61K38/00C07K14/57563A61K38/22A61K38/26A61P3/10C07K14/575C07K14/605
Inventor 高向东赛文博姚文兵杨康敏魏青青宋潇达田浤
Owner CHINA PHARM UNIV
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