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GLP-1/gastrin receptor dual agonist and application thereof

A GLP-1 and receptor technology, applied in the field of GLP-1/gastrin receptor dual agonists, can solve the problems of decreased activity, inability to achieve once-a-week administration, compound immunogenicity, etc., and achieve stability Improvement, excellent hypoglycemic activity and weight loss effect, effect of improving biophysical properties

Active Publication Date: 2021-05-07
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Xinyu Chen et al. revealed a class of conjugated peptides of XenGLP-1 and gastrin-6. However, if the conjugated peptides are administered once a week, the activity will be significantly reduced, so they can only be administered once a day. Unable to achieve weekly dosing
And the required modification method involves a variety of amino acid substitutions, which brings about significant immunogenicity problems of the compound (J.Med.Chem.2020,63, 12595-12613)

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Synthesis of SEQ ID NO:1 polypeptide compound

[0094] His-Aib-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-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH 2

[0095] (1) Swelling of the resin

[0096] 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.

[0097] (2) Removal of resin Fmoc protecting group

[0098] 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 for 15...

Embodiment 2

[0110] Synthesis of SEQ ID NO:2 polypeptide compound

[0111] His-Aib-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-AEEA-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH 2

[0112] The synthesis method was the same as in Example 1, and the target peak was collected and freeze-dried to obtain 0.18 g of the pure product.

Embodiment 3

[0114] Synthesis of SEQ ID NO:3 polypeptide compound

[0115] His-Aib-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-AEEA-AEEA-AEEA-A EEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH 2

[0116] The synthesis method was the same as in Example 1, and the target peak was collected and freeze-dried to obtain 0.19 g of the pure product.

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Abstract

The invention provides a glucagon like peptide-1 (GLP-1) / gastriin receptor dual-excitation polypeptide compound. The GLP-1 / gastriin receptor dual-excitation polypeptide compound disclosed by the invention has more excellent effects of promoting cell proliferation of pancreatic tissues and regeneration of pancreas islets while more effectively reducing blood sugar, and meanwhile, the polypeptide compound has very good effects of reducing weight and treating diabetic nephropathy. The polypeptide compound provided by the invention has a stable chemical property, has the characteristic of low immunogenicity, and is suitable for being used as an active ingredient of medicines for treating metabolic diseases, such as diabetes, obesity, diabetic nephropathy, NAFLD, NASH and the like.

Description

technical field [0001] The invention relates to biomedicine, in particular to a class of GLP-1 / gastrin receptor dual agonists and applications thereof. Background technique [0002] Diabetes mellitus is a metabolic disease characterized by hyperglycemia and one of the most important chronic non-communicable diseases in the world. Diabetes can be divided into insulin-dependent diabetes (type 1 diabetes, T1DM) and non-insulin-dependent diabetes (type 2 diabetes, T2DM), wherein T2DM patients account for more than 85% of the number of diabetic patients. At present, the most effective way to treat T2DM is insulin injection, but there is a risk of hypoglycemia during the treatment. Affected by factors such as dose size, individual differences, injection route, injection site, or not eating after injection, severe hypoglycemia reactions may occur during insulin use. Therefore, finding safe and effective new drugs for hypoglycemia has become an urgent task in the research of curre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P13/12A61P3/04
CPCC07K14/605A61P3/10A61P13/12A61P3/04A61K38/00
Inventor 韩京孟庆华周凤杨启萌
Owner XUZHOU NORMAL UNIVERSITY
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