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GLP-1 similar peptide modified dimer different in configuration and application of preparation method thereof in treating II-type diabetes

A homodimer and monomer technology, applied in the field of medicine and biology, can solve problems such as obvious side effects and effective natural GLP1, and achieve the effects of protecting pancreatic function, increasing the time of hypoglycemic effect, and facilitating clinical application and market promotion.

Active Publication Date: 2020-02-28
深圳纳福生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the side effects are obvious
[0012] GLP-1 analog studies still need to be optimized, as current long-acting activators have proven less effective than Liraglutide or native GLP1 in terms of specific activity (lowering glucose in milligrams), dosing, weight loss, and side effects , for example, in the 26-week trial, Albiglutide lost 0.6 kg compared with Liraglutide's 2.2 kg, and the dulaglutide group lost 2.9 kg compared to 3.6 kg for Liraglutide.

Method used

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  • GLP-1 similar peptide modified dimer different in configuration and application of preparation method thereof in treating II-type diabetes
  • GLP-1 similar peptide modified dimer different in configuration and application of preparation method thereof in treating II-type diabetes
  • GLP-1 similar peptide modified dimer different in configuration and application of preparation method thereof in treating II-type diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The preparation of embodiment 1 monomer peptide and dimer

[0056] 1. Monomer peptide solid-phase synthesis process: Manual solid-phase peptide synthesis operation steps.

[0057] 1. Resin swelling: Put dichloro resin (dichlorobenzyl resin for C-terminal carboxyl group) or amino resin (amino resin for C-terminal amidation sequence) (purchased from Tianjin Nankai Synthetic Technology Co., Ltd.) into In the reaction pot, add dichloromethane (DCM, Dikma Technologies Inc.) 15ml / g resin, shake for 30min. SYMPHONY 12-channel polypeptide synthesizer (SYMPHONY model, software Version.201, Protein Technologies Inc.).

[0058] 2. Connect the first amino acid: Remove the solvent through sand core suction filtration, add 3 times the mole of the first Fmoc-AA amino acid at the C-terminal (all Fmoc-amino acids are provided by Suzhou Tianma Pharmaceutical Group Fine Chemicals Co., Ltd.), and then Add 10-fold molar amounts of 4-dimethylaminopyridine (DMAP) and N,N'-dicyclohexylcarbod...

Embodiment 2

[0083] Example 2 Persistence of the hypoglycemic effect of the GLP-1 monomers and homodimers (G2-9 and 2G2-9 series) of the present invention:

[0084] 1. Experimental method: Normal KM mice were purchased from the Animal Center of Guangdong Province for glucose tolerance test (OGTT) to screen the hypoglycemic activity and persistence of drugs. According to the undifferentiated fasting blood glucose, male Kunming mice (5 weeks old) were divided into multiple groups (NaCl-PB group, Liraglutide group, monomer G2-G9 series and dimer 2G2~2G9 series group) (n=6) . After two rounds of 14-hour feeding-10-hour fasting adaptation period, KM mice were tested for glucose tolerance immediately after each 10-hour fasting. Thirty minutes after subcutaneous injection of the same dose of monomeric or dimer peptides on the back, the mice were orally gavaged with 5% glucose solution, and the blood glucose value of the rat tail was accurately measured at 35 minutes. Blood glucose meters and bl...

Embodiment 3 2

[0096] Embodiment 3 dimer is to the therapeutic effect of type 2 diabetes model

[0097] 1. Construction of type II diabetes (T2D) mouse model

[0098] C57Bl6 / J mice were placed in an SPF-level environment with standard diet and had free access to water. All experiments were performed in accordance with the institutional guidelines for the ethics and use of experimental animals. After feeding with a standard diet for 10 days, 5-week-old C57B16 / J male mice were divided into 6 groups: NaCl-PB, T2D model control group, Liraglutiade, low-middle-high dimer peptide 2G3 or 2G1 group. NaCl-PB group is blank control and T2D model control group is T2D model control, they are injected with NaCl-PB solution. The T2D model group was fed a 60kcal% high-fat diet (D12492, Changzhou Shuyishuerbiotechnology Co., Ltd.) until the end of the experiment, and the blank control group maintained a standard diet until the end of the experiment. The establishment method of the diabetes model: After f...

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Abstract

The invention provides application of novel glucagon peptide 1 fatty acid modified or unmodified dimer different in configuration in pancreas protection or hypoglycemic effect during treatment of II-type diabetes. The dimer is formed by connecting two identical GLP-1 monomers containing cysteine through disulfide bond formed by cysteine oxidation. Hypoglycemic duration of GLP-1 dimer is remarkablyprolonged without lowering activity of H-shaped GLP-1 homodimer (the disulfide bond is formed inside peptide chain), in-vivo continuous activity of GLP-1 analogue dimer can last for 19d while in-vivoactivity of liraglutide which is positive control drug is 3d, or in-vivo activity duration is remarkably prolonged when compared with long-acting GLP1 similar peptide which has already been reportedat present, so that technical progress of long-acting GLP1 drug is greatly promoted while convenience is brought to clinical application and popularization of the same. U-shaped homodimer (the disulfide bond is formed at the terminal C of the peptide chain) does not have impact on blood glucose but can obviously protect exocrine portion cells like pancreatic acini and catheters, thereby having a pancreas protecting function.

Description

technical field [0001] The invention belongs to the field of medicine and biology, and specifically relates to the preparation of various human novel GLP 1-like peptide monomers or homodimers and their application in treating diabetes. Background technique [0002] Glucagon-like peptide 1 (GLP 1) from proglucagon protein is a 30 amino acid residue incretin-like peptide that is released by intestinal L cells upon nutrient intake. It enhances pancreatic β-cell insulin secretion, increases insulin expression and peripheral glucose utilization, inhibits β-cell apoptosis, promotes satiety and β-cell regeneration, reduces glucagon secretion, and delays gastric emptying. These multiple effects make GLP1 receptor agonists significant in the treatment of type 2 diabetes. Currently FDA-approved GLP-1 analogues include Liraglutide (liraglutide) administered once a day, Exenatide administered twice a day, and Albiglutide, Dulaglutide, Exenatide LAR, Lixisenatide, Semaglutide administer...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K19/00A61K38/26A61P3/10
CPCC07K14/605A61P3/10C07K2319/00A61K38/00C07K2319/31A61K38/26A61P1/18
Inventor 唐松山罗群张旭东董玉霞唐婧晅杨莉李玉华葛平戴小敏
Owner 深圳纳福生物医药有限公司
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