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GLP-1/gastrin receptor dual agonist and application thereof

A technology of GLP-1 and gastrin, which is applied in the direction of hormone peptides, glucagon, peptide/protein components, etc., can solve the problems of once-a-week administration and decreased activity, and achieve excellent hypoglycemic activity and stable Sexual improvement, the effect of reversing insulin resistance

Inactive Publication Date: 2022-05-06
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 (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

[0075] Synthesis of polypeptide compound (SEQ ID NO:1)

[0076]

[0077] (1) Swelling of the resin

[0078] 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.

[0079] (2) Removal of resin Fmoc protecting group

[0080] 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 min, and finally the resin was washed with 7 mL of DMF for 4 times, each time for 1.5 min, to obtain the Rink resin from which the Fmoc protecting group was removed.

[0081] (3) Synthe...

Embodiment 2

[0092] Synthesis of polypeptide compound (SEQ ID NO:2)

[0093]

[0094] The synthesis method was the same as in Example 1, and the target peak was collected and freeze-dried to obtain 0.25 g of the pure product.

Embodiment 3

[0096] Determination of agonistic activity of polypeptide compounds on GLP-1 receptor, CCK-1 receptor and CCK-2 receptor

[0097] Agonism of the polypeptide compounds on the receptor was determined by a functional assay, GLP-1 receptor agonistic activity, which measured the cAMP response of the HEK-293 cell line stably expressing the human GLP-1 receptor. Cells stably expressing the GLP-1 receptor were divided into T175 culture flasks and grown overnight in medium (DMEM / 10% FBS) to near confluence, then the medium was removed, and the cells were washed with PBS without calcium and magnesium, and then Protease treatment with Accutase enzyme. Detached cells were washed and resuspended in assay buffer (20 mM HEPES, 0.1% BSA, 2 mM IBMX, 1×HBSS) and cell density was determined and 25 μL aliquots were dispensed into 96-well plates. in the hole. For the measurement, 25 μL of a solution of the test polypeptide compound in assay buffer is added to the wells, followed by incubation at...

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Abstract

The invention provides a type of GLP-1 (Glucagon Like Peptide-1) / gastrin receptor dual-excitation polypeptide compounds. The GLP-1 / gastrin receptor dual-excitation polypeptide compound disclosed by the invention has more excellent effects of promoting cell proliferation and pancreas islet regeneration of pancreatic tissues while more effectively reducing blood sugar, and meanwhile, the polypeptide compound has excellent effects of reducing weight and regulating fat. The polypeptide compound provided by the invention is stable in 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, 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): C07K14/605A61K38/26A61P3/10A61P3/00A61P3/04A61P3/06
CPCC07K14/605A61P3/10A61P3/00A61P3/04A61P3/06A61K38/00
Inventor 韩京周凤
Owner XUZHOU NORMAL UNIVERSITY
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