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GLP-1/glucagon receptor dual agonists and application thereof

A GLP-1 and receptor technology, applied in the field of GLP-1/glucagon receptor dual agonists, can solve problems such as failure to be applied

Active Publication Date: 2021-02-26
南京赛诺生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to its blood sugar-raising effect, GCG also has the effects of promoting lipolysis, fat oxidation, and fever in the body (Diabetologia, 2017, 60, 1851–1861). Long-term administration can show weight loss effects by increasing energy metabolism. However, these beneficial effects of GCG on energy metabolism have not been exploited due to their inherent blood sugar-raising effects

Method used

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  • GLP-1/glucagon receptor dual agonists and application thereof
  • GLP-1/glucagon receptor dual agonists and application thereof
  • GLP-1/glucagon receptor dual agonists and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Synthesis of SEQ ID NO:1 polypeptide compound

[0132] His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH 2 ) 14 -CH 3 )-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2

[0133] (1) Swelling of the resin

[0134] 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.

[0135] (2) Removal of resin Fmoc protecting group

[0136] 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 with the resin fo...

Embodiment 2

[0148] Synthesis of SEQ ID NO:2 polypeptide compound

[0149] His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH 2 ) 14 -CH 3 )-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2

[0150] The synthesis method was the same as in Example 1, and the target peak was collected and lyophilized to obtain 0.16 g of the pure product.

Embodiment 3

[0152] Synthesis of SEQ ID NO:3 polypeptide compound

[0153] His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH 2 ) 14 -CH 3 )-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2

[0154] The synthesis method was the same as in Example 1, and the target peak was collected and freeze-dried to obtain 0.13 g of the pure product.

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PUM

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Abstract

The invention provides a GLP-1 / GCG receptor dual-agonist polypeptide compound. The GLP-1 / GCG receptor dual-agonist polypeptide compound provided by the invention can effectively reduce blood sugar, promote weight loss and prevent weight gain, reverse insulin resistance and regulate lipid metabolism. The polypeptide compound provided by the invention has higher agonistic activity on the GLP-1 receptor and the GCG receptor than natural ligands of each receptor, and has lower agonistic activity on a GIP receptor. The polypeptide compound provided by the invention is stable in chemical property, has low immunogenicity features, 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 / glucagon 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 limited, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00A61K38/16A61P3/10A61P3/04A61P3/06A61P1/16
CPCC07K14/00A61P3/10A61P3/04A61P3/06A61P1/16A61K38/00
Inventor 韩京孟庆华杨启萌
Owner 南京赛诺生物制药有限公司
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