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Specific antagonist peptide for advanced glycation end product receptor as well as derivatives and application of specific antagonist peptide

A technology of advanced glycation and final product, applied in the field of biomedicine, can solve problems such as exceeding endocytosis capacity, damaging nerve cells, affecting mitochondrial function, etc.

Active Publication Date: 2015-05-20
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(3) Aβ-RAGE-endothelial cell inflammation: The interaction between Aβ and RAGE E triggers the generation of ROS and activates the inflammatory pathway, activates NF-kB, and NF-kB acts as a positive feedback to promote the up-regulation of RAGE expression, and the generation of ROS also It will amplify and aggravate the inflammatory process, cause damage and apoptosis of endothelial cells, and eventually destroy the integrity of the BBB, causing damage to the BBB
The specific mechanism of oxidative stress caused by Aβ through mitochondria: (1) Mitochondrial dysfunction caused by mitochondrial dysfunction. In APP transgenic mice, the activity of cytochrome C was found to be weakened. Aβ is also a potent inhibitor of complex IV. AD patients Aβ affects mitochondrial function through the inhibition of different enzymes in the process of energy production in mitochondria, causing mitochondrial dysfunction
(2) Lead to oxidative stress and ROS production: In normal body cells, a small amount of ROS will be produced, and a small amount of ROS has no obvious effect on cells, but in AD patients, neuron cells will produce a large amount of ROS
[0007] Microglia are the most important immune cells in the brain. Under normal conditions, membrane surface receptors such as RAGE and CD47 play a major role in the endocytosis of Aβ, which is the main way for Aβ to be cleared in the brain. Nerve cells have a good protective effect, but in AD patients, due to the massive accumulation of Aβ in the brain, which exceeds the endocytic capacity of microglial cells, excessive Aβ interacts with the microglial membrane surface receptor RAGE to activate the cell Microglia release a large number of pro-inflammatory factors to damage nerve cells and disrupt the stability of the brain environment

Method used

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  • Specific antagonist peptide for advanced glycation end product receptor as well as derivatives and application of specific antagonist peptide
  • Specific antagonist peptide for advanced glycation end product receptor as well as derivatives and application of specific antagonist peptide
  • Specific antagonist peptide for advanced glycation end product receptor as well as derivatives and application of specific antagonist peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Organic Synthesis of Specific Antagonist Peptide for Advanced Glycation End-Product Receptor

[0034] Adopt CS936 peptide synthesizer (USA CSBio company), Fmoc solid-phase synthesis method synthesis (synthesized by Shanghai Qiangyao biological company), the synthesis process includes the following steps:

[0035] (a) Deprotection: use piperidine (piperidine, Shanghai Ziyi Reagent Factory) solution to remove the protecting group of the amino group;

[0036] (b) Activation and cross-linking: the carboxyl group of the next amino acid is activated and dissolved by the activator HBTU (HCTU / HITU)+NMM, and the activated monomer reacts with the free amino group to form a peptide bond;

[0037] (c) cycle: (a), (b) two-step reaction cycle repeatedly until the entire peptide chain is synthesized;

[0038] (d) Elution and deprotection: According to the different residues contained in the peptide chain, it is eluted from the column with different deresin solvents, and its...

Embodiment 2

[0042] Example 2 The specific antagonistic peptide of the advanced glycation end product receptor binds specifically to RAGE on the cell membrane surface of cells with high expression of RAGE

[0043] The advanced glycation end product receptor-specific antagonist peptide prepared in Example 1 was labeled with FITC (Shanghai Qiangyao Biological Co., Ltd.). Confocal plates were seeded with SH-SY5Y-app cells (ATTC, Manassas, VA, USA), 10,000 cells per dish, and cultured in a carbon dioxide incubator for 24 hours (5% CO 2 , 37°C), then washed three times with PBS, fixed with paraformaldehyde for 15 min, washed three times with PBS, blocked with BSA for 1.5 h, and then used FITC-labeled advanced glycation end product receptor specificity at a final concentration of 100 μmol / mL The antagonistic peptide was incubated at room temperature for 2 hours, washed three times with PBST, stained with DAPI, and observed under a laser confocal scanning microscope (Zeiss, Germany). 3T3 cells (S...

Embodiment 3

[0045] Example 3 Advanced Glycation End-Product Receptor Specific Antagonist Peptide Improves the Survival Rate of AD Model Cells

[0046] (1) 3T3 cells were plated in a 96-well plate, with 10,000 cells per well, and cultured for 24 hours (5% CO 2 , 37°C), remove the original medium, add 100 μL of different final concentrations (0, 0.1, 1, 10, 100 μM) of the specific antagonistic peptide of the advanced glycation end product receptor (prepared in Example 1) to each well, After culturing for 48 hours, the cell viability was measured by MTT method, the results are shown in image 3 a.

[0047] (2) Construction of AD model by Aβ: SH-SY5Y-app cells were spread in 96-well plates, 10,000 cells per well, cultured for 24h (5% CO 2 , 37°C), remove the original medium, add 100 μL of Aβ with different final concentrations (0, 25, 50, 100, 200, 400, 800, 1600 μM) to each well (Aβ is diluted with serum-free medium), culture for 48 hours, MTT The cell viability was measured by the method...

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Abstract

The invention belongs to the biomedical field and particularly relates to a specific antagonist peptide for an advanced glycation end product receptor as well as derivatives and an application of the specific antagonist peptide. An amino acid residue sequence of the specific antagonist peptide for the advanced glycation end product receptor is Ala-Pro-Asp-Thr-Lys-Thr-Gln. The derivatives of the specific antagonist peptide are products obtained by conventionally modifying an amino terminal or a carboxyl terminal of a specific antagonist peptide segment on a specific antagonist peptide amino acid side chain group, or products obtained by connecting a label for detecting or purifying polypeptide or protein to the specific antagonist peptide. The specific antagonist peptide of the advanced glycation end product receptor and the derivatives of the specific antagonist peptide can be specifically combined with RAGE in vivo and in vitro, so that neurodegenerative diseases can be treated through the effects of antagonist RAGE, and the relevant mechanism research also can be carried out. The results can be widely applied to the medical and biological fields, so that great social and economic benefits are produced.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a specific antagonistic peptide for receptors of advanced glycation end products, derivatives and applications thereof. Background technique [0002] Receptor for advanced glycation end products (RAGE) is a multi-ligand signal transduction receptor, and its ligands include advanced glycation end products (AGE), β-amyloid protein (Aβ )Wait. RAGE mediates the binding of ligands such as AGE and Aβ on the cell surface, activates a variety of signal transduction mechanisms, and leads to oxidative stress and abnormal cell function. In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease It plays a pivotal role in the pathogenesis of diseases such as PD. [0003] Alzheimer's disease (AD), also known as senile dementia, is a central nervous system lesion that occurs in the early stage of old age and is characterized by progressive cognitive dysfuncti...

Claims

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Application Information

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IPC IPC(8): C07K7/06A61K38/08A61P25/00A61P25/28A61P25/16
Inventor 郑青蔡翠赞代小勇张齐好苏志坚黄亚东
Owner JINAN UNIVERSITY
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