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High-activity exendin-4 analogue and pharmaceutical application thereof

A technology of exenatide and analogs, which is applied in the fields of exenatide analogs and medical applications to achieve the effects of treating or reducing diabetes and obesity, inhibiting gastrointestinal motility and lowering blood sugar

Active Publication Date: 2016-07-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, GLP-1 is easily degraded by dipeptidyl peptidase IV (dipeptidylpeptidase 4, DPP-4) after being secreted into the blood, and its half-life is only 1-2min

Method used

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  • High-activity exendin-4 analogue and pharmaceutical application thereof
  • High-activity exendin-4 analogue and pharmaceutical application thereof
  • High-activity exendin-4 analogue and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Design of Exenatide Analogues

[0041] Design 1: Taking the binding energy of exenatide analogues to GLP-1 receptor as the inspection index, and taking the crystal structure of exenatide binding to GLP-1 receptor (PDBID: 3C5T) (JBiolChem.283(2008)11340) –11347) as the object, using FoldX software (JMolBiol.320(2002)369–387; ProcNatlAcadSciUSA.102(2005)10147–10152) to design, and get several candidate mutants with improved binding energy, including EX-E16W(SEQIDNo :2), EX-R20M (SEQIDNo:16), EX-K27M (SEQIDNo:17) and EX-G29W (SEQIDNo:9).

[0042] Design 2: Because the stability of the α-helical region in the middle of the exenatide molecule has a certain positive correlation with its activity (Biochemistry. 46 (2007) 5830-5840). The design idea is to introduce more intra-chain ionic bonds into the exenatide α-helix to improve its activity. After analyzing the three-dimensional structure of Exenatide, the inventors found that the glutamic acid at positions Leu21 and ...

Embodiment 2

[0045] Example 2 Screening of exenatide analogues in vitro to stimulate insulin secretion activity of rat islet cell tumor cells INS-1

[0046] Rat islet cell tumor cells INS-1 were cultured with RPMI-1640 medium to about 80% confluence, discarded the stock solution, washed twice with PBS buffer, digested with 0.05% trypsin at 37°C for 2 minutes, and used RPMI- containing 10% FBS. The digestion was terminated by 1640, and the cells were collected by centrifugation at 800 rpm for 5 minutes, resuspended in cell culture medium, and then resuspended at 5×10 5 Cells / well are seeded on a 12-well cell culture plate, placed at 37℃, 5% CO 2 Incubate in an incubator for 24 hours, discard the stock solution, and wash once with PBS for experimentation. Experimental grouping: 1. Basal insulin secretion group (containing 0, 30, 60 nM) Exenatide and the serum-free medium of similar drugs designed in Example 1 of the present invention were treated for 24 hours, and each drug concentration was set...

Embodiment 4

[0073] MOE software (Molecular Operating Environment, Chemical Computing Group, Montreal, Canada) was used to analyze the differences between the interactions between mutant EX-E16W, EX-G29W and wild-type exenatide EX-WT and GLP-1 receptor.

[0074] The results showed that, compared with the wild type, the number of interactions between the mutant EX-E16W and EX-G29W and the receptor increased, that is, a new interaction was formed between the mutation site and the receptor.

[0075] Image 6 It is a schematic diagram of the interaction between Glu at position 16 of wild-type Exenatide EX-WT and the receptor. Figure 7 It is a schematic diagram of the interaction between Gly at position 29 of wild-type Exenatide EX-WT and the receptor. Image 6 with Figure 7 It shows that there is no interaction between Glu at position 16 and Gly at position 29 of wild-type exenatide EX-WT and GLP-1 receptor.

[0076] However, in the mutant EX-E16W, the mutated Trp16 forms two new hydrophobic interac...

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Abstract

The invention discloses an exendin-4 analogue.Under stimulation of the analogue, islet cell tumor cells INS-1 of a rat can secrete insulin significantly more actively than that under the simulation of wild exendin-4, and hypoglycemic activity in the body of a diabetic model mouse C57B L / KsJ-db / db is significantly better than that under the simulation of wild exendin-4; the exendin-4 analogue is useful to prevent, treat or alleviate diabetics and obesity as well as other diseases benefiting from glucose reduction, gastrointestinal activity inhibition and gastric emptying.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a class of exendin-4 analogs and medical applications. technical background [0002] Diabetes (diabetesmellitus, DM) is a complex metabolic disease that raises blood sugar due to insufficient insulin secretion or hindered synthesis of insulin in the body leading to endocrine and metabolic disorders. It is mainly divided into type 1 diabetes (type1diabetesmellitus, T1DM) and type 2 diabetes (type2diabetesmellitus). , T2DM) and other types of diabetes. According to statistics, type 2 diabetes accounts for a large proportion, accounting for more than 90% of the total number of diabetic patients. Its onset period is mostly after the age of 35-40, and serious complications will occur in the later stage of the onset. At present, the treatment of diabetes is mainly focused on reducing blood glucose concentration and reducing the occurrence of complications. The treatment method is main...

Claims

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Application Information

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IPC IPC(8): C07K14/575A61K38/22A61P3/10A61P3/04
Inventor 谭树华古丽丽黄传龙王玥许雅琼
Owner CHINA PHARM UNIV
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