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GLP-1/cholecystokin-1 receptor dual agonist and application thereof

A GLP-1 and receptor technology, applied in the field of GLP-1/cholecystokinin-1 receptor dual agonist, can solve problems such as acute pancreatitis

Pending Publication Date: 2021-04-06
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the stimulation of CCK-1 receptors is more likely to lead to the occurrence of acute pancreatitis, which is the main obstacle for CCK-1 receptors as the target receptors of weight-loss drugs. Heavy Drugs Launched

Method used

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  • GLP-1/cholecystokin-1 receptor dual agonist and application thereof
  • GLP-1/cholecystokin-1 receptor dual agonist and application thereof
  • GLP-1/cholecystokin-1 receptor dual agonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Synthesis of SEQ ID NO:1 polypeptide compound

[0112] His-Ala-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys(γ-Glu-CO-(CH 2 ) 14 -CH 3 )-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-AEEA-AEEA-Asp-Phe(4sm)-Nle-Gly-Trp-Nle-DMeAsp-MePhe -NH 2

[0113] (1) Swelling of the resin

[0114] Weigh 0.262g (0.1mmol equivalent) of Rink Amide MBHA resin with a loading capacity of 0.382mmol / g, put it into a 25mL reactor, wash the resin once with 7mL of DCM and methanol alternately, and wash the resin twice with 7mL of DCM , then swell the resin with 7 mL of DCM for 1 h, and finally wash the resin 3 times with 7 mL of DMF.

[0115] (2) Removal of resin Fmoc protecting group

[0116] Transfer the swollen resin to PSI200 peptide synthesizer, add 7mL 20% piperidine / DMF (v / v) to react at room temperature for 5min, filter off the deprotection solution, wash the resin once with 7mL DMF, then add 7mL 20% piperidine / DMF (v / v) The deprotection solvent was reacted w...

Embodiment 2

[0128] Synthesis of SEQ ID NO:2 polypeptide compound

[0129] His-Aib-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys(γ-Glu-CO-(CH 2 ) 14 -CH 3 )-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-AEEA-AEEA-Asp-Phe(4sm)-Nle-Gly-Trp-Nle-DMeAsp-MePhe -NH 2

[0130] The synthesis method was the same as in Example 1, and the target peak was collected and lyophilized to obtain 0.23 g of the pure product.

Embodiment 3

[0132] Synthesis of SEQ ID NO:3 polypeptide compound

[0133] His-Ala-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys(AEEA-AEEA-γ-Glu-CO-(CH 2 ) 16 -COOH)-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-AEEA-AEEA-Asp-Phe(4sm)-Nle-Gly-Trp-Nle-DMeAsp -MePhe-NH 2

[0134] (1) Swelling of the resin

[0135] Weigh 0.262g (0.1mmol equivalent) of Rink Amide MBHA resin with a loading capacity of 0.382mmol / g, put it into a 25mL reactor, wash the resin once with 7mL of DCM and methanol alternately, and wash the resin twice with 7mL of DCM , then swell the resin with 7 mL of DCM for 1 h, and finally wash the resin 3 times with 7 mL of DMF.

[0136] (2) Removal of resin Fmoc protecting group

[0137] Transfer the swollen resin to PSI200 peptide synthesizer, add 7mL 20% piperidine / DMF (v / v) to react at room temperature for 5min, filter off the deprotection solution, wash the resin once with 7mL DMF, then add 7mL 20% piperidine / DMF (v / v) The deprotection solvent was r...

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PUM

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Abstract

The invention provides a GLP-1 / CCK-1 receptor dual-excitation polypeptide compound. The GLP-1 / CCK-1 receptor dual-excitation polypeptide compound has the effects of promoting weight reduction, reversing insulin resistance and regulating lipid metabolism while more effectively reducing blood sugar. The polypeptide compound provided by the invention has higher GLP-1 receptor agonistic activity than the natural ligand, and also has selective agonistic activity to CCK-1 receptor. The polypeptide compound provided by the invention is stable in chemical property and low in side effect, does not cause acute pancreatitis, and is suitable for being used as an active ingredient of medicines for treating metabolic diseases such as diabetes, obesity, hyperlipidemia, NAFLD and NASH.

Description

technical field [0001] The invention relates to biomedicine, in particular to a class of GLP-1 / cholecystokinin-1 receptor dual agonists and applications thereof. Background technique [0002] Obesity and its related metabolic syndrome have become a global public health problem. Many metabolic syndromes such as type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia Both the incidence and the course of the disease are closely related to obesity. Studies have shown that clinically 80-90% of T2DM patients are overweight or obese, and the use of weight loss therapy is beneficial to the prevention and control of the disease, including controlling blood sugar, reducing morbidity and disability (death) rates, etc. It is generally difficult to achieve the ideal weight loss effect only by exercising and diet control to lose weight. At present, the curative effect of the drugs for treating obesity is relatively lim...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/06A61P3/04A61P1/16
CPCC07K14/605A61P3/10A61P3/06A61P3/04A61P1/16A61K38/00
Inventor 韩京孟庆华杨启萌周凤
Owner XUZHOU NORMAL UNIVERSITY
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