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Human glucagon-like peptide-1 receptor activator and application thereof

A technology of glucagon and receptor activator, applied in the field of human glucagon-like peptide-1 receptor activator, can solve the problems of patients with hypoglycemia and weight, and achieve inhibition of expression, improvement of insulin synthesis, inhibition of acetyl Effect of coenzyme A synthase activity

Pending Publication Date: 2021-03-09
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, many antidiabetic drugs can cause patients to experience adverse effects such as hypoglycemia or weight gain

Method used

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  • Human glucagon-like peptide-1 receptor activator and application thereof
  • Human glucagon-like peptide-1 receptor activator and application thereof
  • Human glucagon-like peptide-1 receptor activator and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Affinity Evaluation of Icaritin (ICT) and N-terminal Extracellular Domain of GLP-1R

[0063] The operation method is: using the existing protein crystal structure model (3IOL) on RCSB-PDB, in Schrodinger (Schrödinger) software, based on the fit of ligand and receptor structure, flexible and polar docking mode, evaluate icariin ( ICT) and the affinity of the N-terminal extracellular domain of GLP-1R.

[0064] The docking result is as figure 1 As shown, it can be seen from the figure that: ICT has a docking site in the LYS113-GLU127 domain.

Embodiment 2

[0066] Inhibitory effect of icariin (ICT) on the increase of triglycerides (TGs) in islet cells induced by palmitate (PA) treatment

[0067] The operation method is: use RPMI 1640 medium to cultivate INS-1E cells (rat insulinoma cells) and β-TC6 cells (mouse insulinoma islet β cells) (containing 11.1mM glucose, 10% fetal bovine serum, 10mM HEPES, 2 mM glutamine, 1 mM sodium pyruvate, 100 U / mL penicillin, 100 μg / mL streptomycin and 50 μM β-mercaptoethanol). Palmitate (PA) was dissolved in 0.5% fatty acid-free bovine serum albumin (BSA) solution to a final concentration of 0.5 mM in RPMI 1640. Cells were cultured at 37°C in a humidified incubator containing 5% carbon dioxide. All experiments used cells in logarithmic growth phase. Mouse pancreatic INS-1E and β-TC6 cell lines were treated with 0.5mM PA and ICT (2.5, 5, 10, 20μM) for 48h, respectively.

[0068] The result is as figure 2 with image 3 As shown (in the figure, NC represents the negative control group, PA repre...

Embodiment 3

[0070] Inhibitory Effect of Icaritin (ICT) on Insulin Secretion Reduction in Islet Cells Under High Glucose Stimulation Induced by Palmitate (PA) Treatment

[0071] The operation method is: use RPMI 1640 medium to cultivate (GIBCO, containing 11.1mM glucose) INS-1E cells (rat insulinoma cells) (10% fetal bovine serum, 10mM HEPES, 2mM glutamine, 1mM sodium pyruvate, 100U / mL penicillin, 100 μg / mL streptomycin and 50 μM β-mercaptoethanol). Palmitate (PA) was dissolved in 0.5% fatty acid-free bovine serum albumin (BSA) solution to a final concentration of 0.5 mM in RPMI 1640. Cells were cultured at 37°C in a humidified incubator containing 5% carbon dioxide. All experiments used cells in logarithmic growth phase. Mouse pancreatic INS-1E cell line was treated with 0.5mM PA and ICT (5, 10, 20μM) for 48h respectively.

[0072] The result is as Figure 4 As shown (NC in the figure represents the negative control group), it can be seen from the figure that: ICT can relieve the dec...

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Abstract

The invention relates to a human glucagon-like peptide-1 receptor (GLP-1R) activator and application thereof. The human glucagon-like peptide-1 receptor activator comprises a compound shown in a formula I which is described in the specification or a pharmaceutically acceptable salt of a compound, and R1, R2, R3, R4, R5 and R6 are respectively and independently selected from any one of H, C1-C4 alkyl, sulfydryl, phosphate group, vinyl or acetyl. It is found for the first time that the compound shown in the formula I or the pharmaceutically acceptable salt thereof can improve glycolipid metabolism of whole-body tissue cells, enhance oxidative degradation of lipid molecules, inhibit expression of adipogenic genes, inhibit activity of acetyl coenzyme A synthetase and reduce synthesis of triglyceride, glucose-induced insulin synthesis and secretion are improved, insulin antagonism is relieved, compensatory amplification of pancreatic beta cells is relieved, and the survival rate and functions of pancreatic cells in the II-type diabetes mellitus-like state are improved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a novel human glucagon-like peptide-1 receptor activator and application thereof. Background technique [0002] Diabetes is a chronic, progressive, non-communicable disease characterized by elevated levels of glucose (blood sugar) in the blood, which occurs either because the pancreas cannot secrete enough insulin to regulate blood sugar, or because the body cannot effectively use the insulin it secretes of insulin. Diabetes is a huge burden on healthcare systems and society. [0003] Clinically, type 2 diabetes mellitus (T2DM) is a relatively common progressive disease, and its main features are persistent rise in blood sugar and progressive decrease in β-cell function. Among diabetic patients, type 2 diabetes accounts for The ratio is about 95%. For the treatment of type Ⅱ diabetes, many patients are already in a metabolic disorder state of obesity (overweight...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61P3/06A61P3/10A61P5/50A61P1/16A61P1/18
CPCA61K31/352A61P3/06A61P3/10A61P5/50A61P1/16A61P1/18
Inventor 李尹雄熊月方霁
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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