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Polypeptide organic compound for interference in function of NMDA receptor and application of polypeptide organic compound

A technology of organic compounds and functions, applied in the field of chemistry, can solve the problems that the possibility of functional compensation cannot be ruled out, and it is difficult to correctly reflect functions.

Inactive Publication Date: 2014-10-29
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since such mouse models have completely knocked out a certain NMDA receptor subunit, that is, they do not express a certain protein from the embryonic stage, this cannot rule out the possibility of functional compensation during development , the obtained experimental results are therefore difficult to correctly reflect the true function of these two receptor subtypes in physiological conditions

Method used

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  • Polypeptide organic compound for interference in function of NMDA receptor and application of polypeptide organic compound
  • Polypeptide organic compound for interference in function of NMDA receptor and application of polypeptide organic compound
  • Polypeptide organic compound for interference in function of NMDA receptor and application of polypeptide organic compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Obtaining the polypeptide of the present invention

[0022] Firstly, the ATD domain of GluN2A and the substrate binding domain of Bip were simulated using SWISS-MODEL workshop software. The ATD domain of GluN2A was simulated according to the structure of the homology domain of GluN2B (PDB database ID: 3jpw), and the substrate binding domain of Bip was simulated according to the homology domain of HSP70 (PDB database ID: 4JNF). Further, the interaction between these two domains was simulated, and the amino acids critical to Bip on the ATD domain of GluN2A were identified as points. According to the distribution of these critical points, three polypeptides were designed:

[0023] Polypeptide a is the 137th-147th amino acid, and the sequence is:

[0024] LEU-LYS-ILE-MET-GLN-ASP-TYR-ASP-TRP-HIS-VAL

[0025] Polypeptide b is amino acid 222-232, and its sequence is:

[0026] ARG-SER-LEU-GLY-LEU-THR-GLY-TYR-ASP-PHE-PHE

[0027] Polypeptide c is the 244th-256th ...

Embodiment 2

[0038] Example 2 Peptide interferes with the interaction between endogenous Bip and GluN2A in cultured neurons

[0039] The primary cultured rat cortical neurons were cultured in vitro for 14 days, and 20 μm polypeptide was added to the culture medium, and the culture was continued for 1 hour. Rinse the cells three times with pre-cooled HBSS, add pre-cooled lysate (50 mM Tris-HCl, 0.1 mM PMSF, 1 mM aprotinin, pH7.4) to lyse, and sonicate 8 times at 50% intensity. Add solution A (10% Deoxycholate, pH7.4) to the lysate by 1 / 10 volume, and incubate at 36 degrees for 30 minutes. Then add solution B (500 mM Tris.HCl, 1% Triton X-100, pH9.0) according to 1 / 10 of the volume of the lysate, blow and mix well, and then dialyze at 4 degrees overnight (dialysis solution composition: 50 mM Tris.HCl, 0.1% Triton X-100, pH7.4). During dialysis, the dialysate was changed 2-3 times. After dialysis, the sample solution was collected at 37000 x g and centrifuged at 4°C for 30 minutes. Ke...

Embodiment 3

[0040] Example 3 Peptide interferes with the interaction between endogenous Bip and GluN2A in the hippocampus

[0041] The mice were intraperitoneally injected with Polypeptide B at a dosage of 10 per kg . One hour after the injection, the hippocampal region of the mouse brain was taken, and 1 ml of pre-cooled lysate was added for every 0.5 g, and the brain tissue was lysed with a homogenizer. Centrifuge at 700 x g for 10 minutes, take the supernatant, add solution A (10% Deoxycholate, pH7.4) at 1 / 10 volume, and then detect the interaction between Bip and GluN2A according to the method of co-immunoprecipitation of cells. It was detected that Bip and GluN2A in the hippocampus of the mouse brain were effectively separated, and it was found that polypeptide B could effectively interfere with the interaction between GluN2A and Bip. The control polypeptide had no such effect. See results figure 2 .

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Abstract

The invention provides an application of a polypeptide organic compound for interference in the function of an NMDA receptor in researches of learning and memory of mammals. The polypeptide organic compound is selected from A, B or C and can be used for effectively inhibiting an expression of a GluN2A-NMDA receptor induced by neuron activities, i.e., the polypeptide organic compound is a general mechanism affecting plasticity, so that the polypeptide organic compound can be applied to the preparation of therapeutic medicines for neuropsychological diseases relevant to the abnormal learning and memory mechanism. The polypeptide organic compound can perform effective interference in formation of conditioned fear memories, so that the polypeptide organic compound can be applied to the preparation of the therapeutic medicines relevant to post-traumatic stress disorder. The polypeptide organic compound can perform effective interference in the synaptic expression of the GluN2A-NMDA receptor induced by plasticity stimulus so as to affect learning and memory processes. The polypeptide organic compound is low in effective dose, cannot generate toxic and side effects on animals and has high specificity. As a result, the relevant researches can be carried out by utilizing the polypeptide organic compound to a maximum extent.

Description

technical field [0001] The invention belongs to the field of chemistry and relates to providing a polypeptide organic compound that interferes with the function of NMDA receptors and its application in the field of biomedicine. technical background [0002] Learning and memory are important brain functions in mammals, and abnormal learning and memory are also the basis of some neuropsychiatric disorders. Research on its biological mechanism involves multiple organizational levels such as molecules, synapses, circuits, systems, wholes and behaviors. [0003] At present, it is believed that the cellular mechanism of learning and memory is the change of synaptic plasticity and its neural circuit function, such as long-term potentiation and long-term weakening. At the molecular and cellular level, this neuronal synaptic plasticity change is mainly manifested as the strengthening or weakening of synaptic transmission efficiency, including the release efficiency of presynaptic tr...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/08A61K38/10A61K47/48A61P25/00A61P43/00
Inventor 罗建红张筱敏朱丽君邱爽叶茂严循一张斌曹蔚杨倩
Owner ZHEJIANG UNIV
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