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Glucagons like peptide-1 (GLP-1) analog and application thereof

A technology of glucagon and GLP-1, which is applied in the field of glucagon-like peptide-1 analogs, can solve the problems of GLP-1 loss of biological activity, loss of histidine residues, etc., and achieve convenient purification work, Improved stability, easy to automate effects

Active Publication Date: 2011-09-14
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The N-terminus of the GLP-1 molecule is the binding site with the GLP-1 receptor, and its histidine residue is lost, resulting in the complete loss of biological activity of GLP-1

Method used

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  • Glucagons like peptide-1 (GLP-1) analog and application thereof
  • Glucagons like peptide-1 (GLP-1) analog and application thereof
  • Glucagons like peptide-1 (GLP-1) analog and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Chemically Modified Cys-Ala-Ala-Lys-Glu-Phe-Ile-Ala -Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ. ID NO: 2)

[0057] microwave-facilitated solid-phase synthesis

[0058] (1) Swelling of the resin

[0059] Weigh 50 mg of Fmoc-Rink amide-MBHA Resin (substitution amount 0.4 mmol / g), swell with 7 mL of DCM for 30 min, filter to remove DCM, then swell with 10 mL of NMP for 30 min, and finally rinse with NMP, DCM, and 7 mL of NMP respectively.

[0060] (2) Microwave promotes removal of Fmoc protecting group

[0061] Put the swollen resin into the reactor, add 7mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT, react in the microwave reactor for 1min, the microwave power is 15W, and the reaction temperature is controlled at 50°C Within the time period, use an air compressor to compress the air to cool, and filter the solution after the reaction; add 7 mL of 25% piperidine / NMP (V / V) solution containing 0.1M HO...

Embodiment 2～6

[0096] According to the method described in Example 1, the glucagon-like peptide-1 (GLP-1) analogues of Examples 2-6 were synthesized according to the corresponding sequence, and the respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS) .

Embodiment 2

[0098] His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Chemically Modified Cys-Ala-Ala-Lys-Glu-Phe-Ile-Ala -Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ. ID NO: 3);

[0099] The theoretical relative molecular mass is 3850.8. ESI-MS m / z: found[M+4H] 4+ 963.7, [M+5H] 5+ 771.2;calu[M+4H] 4+ 963.7, [M+5H] 5+ 771.2.

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PUM

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Abstract

The invention relates to a novel long-acting glucagons like peptide-1 (GLP-1) analog and a synthesis method thereof. The synthesis method comprises the following steps: modifying the 8th, 23rd or 37th site of the natural GLP-1 to obtain the GLP-1 analog having longer pharmacological action time; quickly synthesizing a peptide chain by adopting a microwave-promoted solid-phase synthesis method; reacting cysteine residues with a 4-hydroxyl coumarin analog to obtain a target polypeptide; purifying the crude product; and carrying out freeze-drying to obtain the GLP-1 analog.

Description

technical field [0001] The present invention relates to glucagon-like peptide-1 (GLP-1) analogs and applications thereof. Background technique [0002] Diabetes is the third chronic non-communicable disease that seriously threatens human health after tumors and cardiovascular diseases. Currently, there are about 300 million diabetics in the world, which is expected to increase to 500 million by 2025. In 2010, there were 92 million diabetics in China, and China has become the second largest country with diabetes after India, in which type 2 diabetes accounts for about 90% of the total number of diabetics. The most effective way to treat type 2 diabetes right now is insulin injections. Clinically, intensive insulin therapy is used to delay the progression of diabetes. Insulin therapy can reverse the damage of pancreatic β-cell function to a certain extent while lowering blood sugar. However, there is a risk of hypoglycemia with insulin. Affected by factors such as dose siz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04A61K38/26A61P3/10
Inventor 黄文龙钱海韩京倪帅健陈巍赵鑫鑫杨宝卫朱孝云
Owner CHINA PHARM UNIV
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