Long-acting blood sugar-lowering and weight-reducing peptide, preparation method and application thereof

A compound and peptide resin technology, applied in the field of long-acting oxyntomodulin hybrid peptides, can solve the problems of short half-life and weak hypoglycemic activity, and achieve the effects of simple steps, easy purification and improved yield

Active Publication Date: 2018-11-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with pure GLP-1R agonists, OXM has a better effect in intervening body weight, regulating lipid metabolism, and improving glucose tolerance, but its hypoglycemic activity is relatively weak and its half-life is short

Method used

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  • Long-acting blood sugar-lowering and weight-reducing peptide, preparation method and application thereof
  • Long-acting blood sugar-lowering and weight-reducing peptide, preparation method and application thereof
  • Long-acting blood sugar-lowering and weight-reducing peptide, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080]

[0081] Solid phase synthesis

[0082] 1. Synthesis of peptide backbone

[0083] 1.1 Swelling of resin

[0084] Weigh 50mg of Fmoc-Rink amide-MBHA Resin (degree of substitution 0.4mmol / g), swell with 7mL of DCM for 30min, filter to remove DCM, then swell with 10mL of NMP for 30min, and rinse with NMP and 7mL of DCM respectively.

[0085] 1.2 Removal of Fmoc protecting group

[0086] Put the swollen resin into the reactor, add a 25% piperidine / NMP (V / V) solution containing 0.1M HOBt to the resin to remove Fmoc, and wash it with NMP after the reaction. The result is a resin from which the initially attached Fmoc protecting group is removed.

[0087] 1.3 Synthesis of Fmoc-Ser(tBu)-Rink amide-MBHA Resin

[0088] Dissolve Fmoc-Ser(tBu)-OH (15.4 mg, 0.04 mmol), HBTU (15.1 mg, 0.04 mmol), HOBt (5.4 mg, 0.04 mmol) and DIPEA (13.9 μL, 0.08 mmol) in 10 mL of NMP, and then This solution was added to the resin obtained in the previous step to react for 2 hours. After completion, the reactio...

Embodiment 2

[0096]

[0097] The synthesis method was the same as in Example 1. The collected solution was lyophilized to obtain 29.9 mg of pure product. The theoretical relative molecular mass is 4662.3. ESI-MS m / z: Calcd.[M+3H] 3+ 1555.1, [M+4H] 4+ 1166.6; Found[M+3H] 3+ 1555.7, [M+4H] 4+ 1166.1.

Embodiment 3

[0099]

[0100] The synthesis method is the same as in Example 1, and the collected solution is lyophilized to obtain 30.4 mg of pure product. The theoretical relative molecular mass is 4621.2. ESI-MS m / z: Calcd.[M+3H] 3+ 1541.4, [M+4H] 4+ 1156.3; Found[M+3H] 3+ 1541.9, [M+4H] 4+ 1156.7.

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PUM

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Abstract

The invention relates to a long-acting blood sugar-lowering and weight-reducing oxyntomodulin (OXM) hybrid peptide, application and a synthesis method thereof. Through modification of OXM, heterozygosis with the peptide sequence of Exenatide, and conjugation with micromolecule aliphatic chain, the OXM hybrid peptide with longer pharmacological action time and better weight losing effect can be obtained. Synthesis of the target polypeptide is quickly achieved by solid-phase synthesis method, and a crude product is purified and lyophilized so as to obtain the target compound.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a long-acting oxyntomodulin (OXM) hybrid peptide and its application. Background technique [0002] The cause of metabolic syndrome is abnormal metabolism of protein, fat and carbohydrates. Overnutrition and reduced physical activity can lead to obesity and obesity-related diseases such as diabetes. In recent years, the incidence of type 2 diabetes and abnormal blood lipid metabolism has been increasing. [0003] Oxyntomodulin (Oxyntomodulin, OXM) is a 37-amino acid peptide secreted by small intestinal L cells, including all 29 amino acid sequences of glucagon and 8 amino acid parts extending from the C-terminal, similar to glucagon Peptide-1 (GLP-1) has 50% homology, and the peptide sequence is: HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA. OXM can activate glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) at the same time, and has a certain effect on slowing weight ...

Claims

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Application Information

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IPC IPC(8): C07K19/00C07K1/06C07K1/04A61K38/22A61K38/26A61P3/10A61P3/04A61P3/06A61P1/16
CPCA61K38/00A61P1/16A61P3/04A61P3/06A61P3/10C07K14/57563C07K14/605C07K2319/00A61K9/0019A61K9/006A61K9/0073A61K9/0095A61K9/02A61K9/107A61K9/12A61K9/1605A61K9/2004A61K9/4841A61K9/7007A61K9/7015A61K9/7023
Inventor 钱海黄文龙李承业蔡星光刘春霞孙李丹戴雨轩
Owner CHINA PHARM UNIV
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