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DR8 polypeptide analogue as well as preparation method and application thereof

A technology of analogs and drugs, applied in the field of biochemistry, can solve the problems such as the need to improve the drug efficacy, the poor stability of DR8, and the low bioavailability

Pending Publication Date: 2021-12-31
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results of using DR8 in the treatment of pulmonary fibrosis and renal fibrosis in the prior art show that DR8 can effectively improve lung and renal fibrosis, but DR8 still has problems of poor stability, low bioavailability, and drug efficacy that needs to be improved

Method used

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  • DR8 polypeptide analogue as well as preparation method and application thereof
  • DR8 polypeptide analogue as well as preparation method and application thereof
  • DR8 polypeptide analogue as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Embodiment 1, the preparation of compound

[0082] Step 1: The synthesis of the compound adopts the Fmoc solid-phase synthesis method, and is synthesized from the carboxyl terminal to the amino terminal direction. The specific steps are as follows:

[0083] (1) Activation of MBHA resin: Weigh the resin and add an appropriate amount of DCM to swell on the shaker for 30 minutes, drain and add DMF to wash 3 times, each time for 3 minutes;

[0084] (2) Indene test: add ninhydrin: pyridine: phenol = 1:2:1 indene test reagent in the test tube, dip a little resin in it, and bathe in boiling water for 3 minutes. If the indene test result is yellow, it indicates that the resin is normal;

[0085] (3) Resin deprotection: add DMF solution containing 3% double-distilled piperidine to remove the protective group, remove the residual reagent, add DMF to wash, 3 min each time, repeat 4 times, and remove the residual reagent;

[0086] (4) Indene test: add ninhydrin: pyridine: phenol =...

Embodiment 2

[0102] Embodiment 2, using the compound obtained in Embodiment 1 as the test substance to carry out the in vitro activity screening experiment of fibrosis

[0103] The mouse embryonic fibroblast NIH3T3 cell line was selected to study and observe the effect of the test substance on the expression of α-smooth muscle actin (α-smooth muscle actin, α-SMA) in NIH3T3 cells induced by transforming growth factor TGF-β1.

[0104] NIH3T3 cells were plated in 6-well plates with DMEM + 10% FBS + 1% double antibody medium (ThermoFisher) at 37°C, 5% CO 2 After culturing for 24 hours under the same conditions, replace it with serum-free medium for 12 hours, add 5ng / mL LTGF-β1 and 80μM test substance to act on the cells for 48 hours, extract the total protein of the cells, and detect the protein expression level of α-SMA by Western blot.

[0105] Experiments include:

[0106] Blank control group( figure 1 Marked as Control, TGF-β1 and test substance were not added in the culture medium);

...

Embodiment 3

[0114] Example 3. The compounds DR8-3D, DR8-8A, DR3penA, DR4penA and DR7dA obtained in Example 1 were used as test substances to perform in vitro inhibitory effect experiments on fibrosis

[0115] Human lung adenocarcinoma cell line A549, renal tubular epithelial cell line HK-2 and embryonic fibroblast cell line NIH3T3 were selected to study and observe the effects of test substances on the expression of fibrosis-related proteins in different cells.

[0116] A549 cells, HK-2 cells and NIH3T3 cells were respectively plated in 6-well plates, and RPMI1640+10% FBS+1% double-antibody medium, DMEM / F12+10% FBS+1% double-antibody medium and DMEM+ 10% FBS+1% double antibody medium at 37°C, 5% CO 2 Cultivate for 24 hours under the same conditions, replace with serum-free medium for 12 hours, add 5ng / mL LTGF-β1 and different concentrations of test substances to act on A549 cells or NIH3T3 cells for 48 hours, or act on HK-2 cells for 24 hours, then extract the total cell protein, and dete...

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Abstract

The invention belongs to the technical field of biochemistry, and particularly relates to a DR8 polypeptide analogue which can be used for treating or preventing pulmonary fibrosis, renal fibrosis and other related diseases as well as a preparation method and application of the DR8 polypeptide analogue. The amino acid sequence of the DR8 polypeptide analogue disclosed by the invention is as follows: NH<2>-Asp-His-Xaa3-Xaa4-Pro-Gln-Xaa7-Xaa8-CONH<2>, in the formula, Xaa3 is Ala, D-Asn or alpha-(4-Pentenyl)-Ala; xaa 4 is Ala, D-Asn or alpha-(4-Pentenyl)-Ala; xaa7 is Ala or D-Ala; and Xaa8 is Ala or D-Arg. The DR8 polypeptide analogue disclosed by the invention is low in dosage, high in stability, safe, non-toxic, low in preparation cost and higher in generalizability; the problems that DR8 is poor in stability, low in bioavailability and low in drug effect are solved.

Description

technical field [0001] The present invention belongs to the technical field of biochemistry, and specifically relates to a DR8 polypeptide analog, and the present invention also relates to a preparation method of the DR8 polypeptide analog and its prevention and / or treatment in related diseases such as pulmonary fibrosis and renal fibrosis use in . Background technique [0002] Pulmonary fibrosis (PF) is a common pathological change of increased fibrous connective tissue and decreased parenchymal cells in lung tissue caused by various acute and chronic diseases, and it develops progressively. Pulmonary failure caused by fibrosis is the main cause of disability and death of patients, and the median survival time of patients after diagnosis is only 3-5 years. With the continuous deterioration of the atmospheric environment, the increasing number of radiological examinations, treatments and chemical drug treatments for various diseases, the incidence rate has been increasing y...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P11/00A61P13/12
CPCC07K7/06A61P11/00A61P13/12A61K38/00Y02P20/55
Inventor 谢俊秋王锐王丹张邦治邓铂川成露
Owner LANZHOU UNIVERSITY
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