Application of beta-hydroxypyruvic acid in preparation of human islet amyloid polypeptide aggregation inhibitor

A hydroxypyruvate and amyloid polypeptide technology, which can be used in the fields of anhydride/acid/halide active ingredients, metabolic diseases, drug combinations, etc., and can solve the problems of restriction, low bioavailability and low gastrointestinal absorption rate.

Inactive Publication Date: 2021-05-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently available small molecule inhibitors are mostly derived from chemical synthesis or extracted from natural products, and their bioavailability and gastrointestinal absorption rate are low, which limits their effects in vivo

Method used

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  • Application of beta-hydroxypyruvic acid in preparation of human islet amyloid polypeptide aggregation inhibitor
  • Application of beta-hydroxypyruvic acid in preparation of human islet amyloid polypeptide aggregation inhibitor
  • Application of beta-hydroxypyruvic acid in preparation of human islet amyloid polypeptide aggregation inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] In this example, transmission electron microscopy is used to characterize the effect of candidate metabolites on the morphology of fibers formed by IAPP aggregation.

[0023] 1. IAPP dispersion method: Weigh 4.74mg IAPP, measure 2.456mL HFIP to dissolve, the concentration is 0.5mM, ultrasonic for 2 minutes.

[0024] 2. Prepare 2.5×PBS (containing 50mM NaCl) solution: weigh 0.2g KCl, 1.1688g NaCl, 0.22gKH 2 PO 4 ,2.08g Na 2 HPO 4 12H 2 O, measure 250mL ultrapure water to dissolve it completely.

[0025] 3. Preparation of HPA stock solution: Weigh 5 mg of HPA, add 600 μL of the above-mentioned 2.5×PBS (containing 50 mM NaCl) solution, dissolve it, and prepare 80 mM HPA stock solution.

[0026] 4. Prepare 3-methyl-L-histidine stock solution: weigh 1mg of 3-methyl-L-histidine, add 739μL of the above-mentioned 2.5×PBS (containing 50mM NaCl) solution, dissolve it, and prepare Make 8mM 3-methyl-L-histidine stock solution.

[0027] 5. Preparation of 3-hydroxybutyric acid...

Embodiment 2

[0035] In this example, ThT staining was used to characterize the regulation of HPA on the aggregation ability of IAPP by fluorescence spectrophotometry.

[0036] 1. Prepare 2.5×PBS (containing 50mM NaCl) solution: weigh 0.2g KCl, 1.1688g NaCl, 0.22gKH 2 PO 4 ,2.08g Na 2 HPO 4 12H 2O, measure 250mL ultrapure water to dissolve it completely.

[0037] 2. Prepare ThT stock solution: Weigh 1.25mg ThT and dissolve it in 1.960mL ultrapure water.

[0038] 3. HPA stock solution method: as described in Example 1.

[0039] 4. IAPP dispersion method: as described in Example 1.

[0040] 5. Measure 500 μL of the above-prepared dispersed IAPP stock solution and add it to 49.5 mL of the above-mentioned 2.5×PBS (containing 50 mM NaCl) to prepare a control group.

[0041] 6. Take 16 μL of HPA stock solution, add it to 49.484 mL of 2.5×PBS (50 mM NaCl), mix with 500 μL of the dispersed IAPP stock solution prepared above, and prepare HPA:IAPP 5:1 group.

[0042] 7. Take 32 μL of HPA stoc...

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PUM

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Abstract

The invention discloses application of an endogenous metabolite beta-hydroxypyruvic acid (HPA) in preparation of a human islet amyloid protein (IAPP) aggregation inhibitor. A differential metabolite HPA with the potential of inhibiting IAPP fibrosis is screened by taking an endogenous metabolite as a target, and the ThT method detection shows that the HPA acts on an IAPP oligomer formation stage, so that the generation speed of an IAPP oligomer is remarkably delayed, the content of a beta folding structure is reduced, and the function of inhibiting fibrosis is achieved. According to TEM characterization, the morphology of fibers formed after action with HPA is remarkably changed, no typical IAPP fibers are generated, HPA can effectively inhibit IAPP fibrosis, and the application has very important significance for finding and designing drugs for inhibiting IAPP aggregation and physiological toxicity caused by IAPP aggregation.

Description

technical field [0001] The invention belongs to biomedicine technology, and specifically relates to the application of beta-hydroxypyruvate in the preparation of inhibitors of human islet amyloid polypeptide aggregation. Background technique [0002] The aggregation of human islet amyloid polypeptide (IAPP, Human islet amyloid polypeptide) is considered to be closely related to the occurrence and development of type II diabetes (T2DM). Studies have shown that the metabolic disorder caused by T2DM can lead to the misfolding and aggregation of IAPP, and the formed fibrous deposition will further lead to the dysfunction of islet β cells, causing cellular oxidative stress, endoplasmic reticulum stress and mitochondrial damage by inducing intracellular oxidative stress. toxicity. Therefore, inhibiting the aggregation of IAPP is of great significance for the prevention and treatment of T2DM. At present, progress has been made in research on therapeutic methods aimed at delaying ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/19A61P3/10
CPCA61K31/19A61P3/10
Inventor 郝海平郑秋凌夏丹丹杨蕾徐小为
Owner CHINA PHARM UNIV
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