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Fusion polypeptide and its application in the preparation of antidepressant and neurodegenerative disease drugs

A fusion peptide and anti-depressant technology, applied in nervous system diseases, hybrid peptides, drug combinations, etc., can solve problems such as limitations, low oral utilization, short half-life, etc., and achieve safe use, good transmembrane efficiency, and stability good effect

Active Publication Date: 2020-12-04
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as we all know, due to its own characteristics, peptide drugs have many shortcomings, such as low oral utilization, high enzymolysis and extremely short half-life, etc., which make them suffer from many restrictions in drug development.

Method used

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  • Fusion polypeptide and its application in the preparation of antidepressant and neurodegenerative disease drugs
  • Fusion polypeptide and its application in the preparation of antidepressant and neurodegenerative disease drugs
  • Fusion polypeptide and its application in the preparation of antidepressant and neurodegenerative disease drugs

Examples

Experimental program
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Effect test

Embodiment 1

[0065] In this example, in the preliminary experimental design, the inventors screened four domains (eIF4A-Q, eIF4A-I, eIF4A-Ia, eIF4A-VI) in which eIF4A tightly binds to PDCD4 by referring to the literature, and the amino acid sequences thereof are shown in the table 1 shown. By the method of molecular cloning, the inventors constructed a fusion protein containing the target domain ( figure 1 a figure 1 b). Co-immunoprecipitation ( figure 1 c) The results showed that the IB:HA band in the eIF4A-VI group was significantly lower than other domains, almost colorless, which proved that the eIF4A in the eIF4A-VI interference group had almost no interaction with PDCD4, and the eIF4A-VI had a good interference efficiency. At the same time, immunoblotting experiments ( figure 1 d) It is verified that eIF4A-VI can induce the expression of IIc-BDNF, and the induction effect is also significantly higher than that of other domain polypeptides. eIF4A-VI can also interfere with the bin...

Embodiment 2

[0069] Combined with the research results of Example 1, in this example, eIF4A-VI was selected for corresponding modification, and the polypeptide 9R-eIF4A-VI was synthesized by adding a 9R transmembrane sequence at the N-terminus. like figure 2 As shown in a, the N-terminal of the fusion polypeptide is a 9R transmembrane sequence, and the C-terminal is the eIF4A-VI domain obtained by screening. The 9R transmembrane sequence and the 9R-eIF4A-VI sequence are shown in Table 2 below:

[0070] Table 2 9R and 9R-eIF4A-VI amino acid sequences

[0071]

[0072] In order to test the effect of the fusion polypeptide on interfering with the binding of PDCD4 to eIF4A, the inventors designed 9R-mueIF4A-VI as a control peptide for testing. Compared with 9R-eIF4A-VI, the 9R-mueIF4A-VI randomly mutated an amino acid at one site. ( figure 2 b / 2c / 2d) It was confirmed by immunoblotting experiment that 9R-eIF4A-VI can promote the expression of IIc-BDNF, and the promoting effect is concen...

Embodiment 3

[0079] Example 2 has confirmed that the 9R-eIF4A-VI has good transmembrane effect and stability in the HEK-293 cell model. This example further studies the effect of the polypeptide on neuronal cells.

[0080] like image 3 As shown in a, the inventors also verified the transmembrane efficiency and stability of 9R-eIF4A-VI in primary neuron cells. like image 3 b, In primary neurons, fluorescence observation showed that 9R-eIF4A-VI and PDCD4 had obvious co-localization, which further explained the specific interference of this polypeptide sequence on PDCD4. image 3 C shows that in primary neurons, 9R-eIF4A-VI can promote the expression of BDNF. ( image 3 d) The expression of BDNF in the supernatant of primary neuron culture was detected by ELISA, and the purpose of the inventor's design to increase the expression of BDNF by interfering with the combination of PDCD4 and EIF4A to enhance the signal transmission between synapses and relieve depression symptoms .

[0081] A...

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Abstract

The invention belongs to the technical field of biology, and specifically relates to a 9R-eIF4A-VI fusion polypeptide and an application of fusion polypeptide in preparing a medicine for anti-depression. The studies confirm that PDCD4 can bind to a eukaryotic translation initiation factor (eIF4A) to inhibit the expression of a brain-derived neurotrophic factor (BDNF), impedes the repair and synaptic transmission of damaged neurons, and aggravates the symptoms of the depressed patients. The application screens a number of domains in which PDCD4 binds to eIF4A, by fusion of a transmembrane sequence and a domain on eIF4A, the fusion polypeptide having the interference effect is obtained, the experiments verify that the fusion polypeptide can effectively interfere with the binding of PDCD4 and eIF4A, has good transmembrane efficiency and stability, and can be applied to the preparation of antidepressant drugs, which has great significance.

Description

technical field [0001] The present disclosure belongs to the field of biotechnology, and in particular relates to the application of a polypeptide interfering with the combination of PDCD4 and eIF4A and the fusion polypeptide 9R-eIF4A-VI as antidepressant and anti-neurodegenerative disease drugs. Background technique [0002] The disclosure of information in this Background section is only for enhancement of understanding of the general background of the disclosure and should not necessarily be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. [0003] Depression is a type of mental disorder with depression as the main symptom. Severe patients even have suicidal behavior, which seriously threatens human health. A large number of clinical studies have shown that synaptic plasticity caused by excessive activation of microglia is the pathological basis of depression. Brain-der...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K38/17A61K47/64A61P25/24
CPCA61K38/00A61P25/24C07K14/4705C07K2319/03
Inventor 张利宁贾玉峰李媛王群朱法良郭春李艳
Owner SHANDONG UNIV
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