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Preparation of compound of Au and anti-apoptotic protein antagonistic peptide and application of compound in synergistic induction of tumor cell apoptosis

A technology of anti-apoptotic proteins and complexes, applied in the field of anti-tumor drugs, can solve the problems of no reported synthetic methods of gold and anti-apoptotic protein antagonistic peptide complexes, etc., to reduce the effective dose of drugs, reduce toxic and side effects, and improve The effect of drug efficacy

Active Publication Date: 2022-05-06
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no report on the synthesis method of gold and anti-apoptotic protein antagonistic peptide complex and its effect on tumor growth inhibition

Method used

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  • Preparation of compound of Au and anti-apoptotic protein antagonistic peptide and application of compound in synergistic induction of tumor cell apoptosis
  • Preparation of compound of Au and anti-apoptotic protein antagonistic peptide and application of compound in synergistic induction of tumor cell apoptosis
  • Preparation of compound of Au and anti-apoptotic protein antagonistic peptide and application of compound in synergistic induction of tumor cell apoptosis

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Experimental program
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preparation example Construction

[0031] A method for preparing a novel single-drug synergistic anti-tumor drug AuP complex according to an embodiment of the present invention, comprising:

[0032] Mix the gold salt solution with the anti-apoptotic protein antagonist peptide solution containing sulfhydryl groups, and stir for 3 to 5 minutes to make the gold salt and the polypeptide fully contact to form a mixed solution; add a reducing agent to the above mixed solution to make the system undergo redox After the reaction, the solution was stirred for 5min-2h after the color of the solution turned light yellow, and then stood at room temperature in the dark for 24-48h, and finally a complex of gold and peptide was obtained.

[0033] Further, the above complex can be removed with a centrifuge to remove large particles, and then purified with an ultrafiltration tube to remove unreacted alkali and unreacted gold salt, and then concentrated for future use.

[0034] Wherein, the molar ratio of gold salt and thiol pol...

Embodiment 1

[0041] Embodiment 1, preparation and characterization of AuP complex

[0042] Dissolve 10 mg of BAD peptide in 5 mL of deionized water, then add 85.5 μL of 25 mM chloroauric acid solution, and stir for 3 min in the dark, until the color of the solution changes from yellow to light yellow, then add trisodium citrate solution to the system, and stir for 5 min. Store at room temperature protected from light for two days. Use an ultrafiltration tube with a molecular weight cut-off of 10,000 to remove free metal ions and unreacted small peptides. The synthesized complex is pale yellow and almost colorless under visible light. It appears blue under ultraviolet light.

[0043] Such as Figure 1a As shown, the BAD peptide has a strong absorption peak at 278nm, and the complex is an absorption platform at 275nm, and the intensity becomes higher, indicating that the BAD peptide has reacted. Such as Figure 1b As shown, the fluorescence spectrum of the complex shows that the optimum ...

Embodiment 2

[0045] Example 2. Cytotoxicity and apoptosis induction of AuP on MEC-1 cells

[0046] MEC-1 cells were seeded on a 96-well plate at 10,000 cells / well. After culturing for several hours, a series of concentration gradients of AuP were added to the cell wells. The doses of gold were 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM. , and then incubated in the dark for 48h, with 3 samples in parallel for each group. After incubation for 48 hours, incubate the cells with a solution of cck-8 ratio of 1:10 (volume ratio) in the dark for 1-2 hours, and finally, use a microplate reader to read the absorbance of each well at 450 nm to calculate the cell survival Rate. The result is as Figure 2a As shown, AuP has obvious inhibitory effect on chronic lymphocytic leukemia cells, and the IC50 value is between 20μM-30μM.

[0047] AuP induced apoptosis of chronic lymphocytic leukemia cells Figure 2b As shown, the cell drug treatment method is the same as the cytotoxicity experiment. After the tre...

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Abstract

The invention discloses preparation of a compound of Au and an anti-apoptotic protein antagonistic peptide and application of the compound in synergistic induction of tumor cell apoptosis, and relates to the field of anti-tumor drugs. Mixing a gold salt solution with the anti-apoptotic protein antagonistic peptide containing sulfydryl; under the conditions of certain temperature and pH, redox reaction is carried out, high-valence Au ions are reduced into Au atoms or monovalent Au ions, and Au acts on sulfydryl of polypeptide to form a compound AuP; the sulfydryl-containing anti-apoptotic protein antagonistic peptide is selected from polypeptides with an intracellular anti-apoptotic protein antagonistic function. The AuP compound has broad-spectrum anti-tumor activity, and compared with a common peptide-gold compound or gold compound, the AuP compound can inhibit the activity of thioredoxin reductase and antagonize the function of high-expression anti-apoptotic protein at the same time, the single-drug double-target synergistic effect is achieved, and the curative effect is remarkably improved. The compound can be used for treating various malignant tumors such as chronic lymphocytic leukemia, acute monocytic leukemia and non-Hodgkin lymphoma.

Description

technical field [0001] The invention relates to the field of antitumor drugs, in particular to a preparation method of a polypeptide-Au complex that can be used for the treatment of malignant tumors such as chronic lymphocytic leukemia and the application of the complex in synergistically inducing apoptosis in tumor cells. Background technique [0002] Compared with normal tissue cells, a variety of malignant tumor cells (such as chronic lymphocytic leukemia cells) have higher intracellular reactive oxygen species (ROS) levels, which put the cells under oxidative stress. Drugs that induce elevated reactive oxygen species more sensitive. Thioredoxin reductase (TrxR) is the most important enzyme in regulating redox balance in mammalian cells, and has become an effective target for the treatment of this type of tumor. However, some tumor cells highly express mitochondrial anti-apoptotic proteins (such as BCL-2), which can resist the apoptosis induced by chemotherapy drugs. Us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/242A61K38/16A61P35/02A61P35/00
CPCA61K33/242A61K38/16A61P35/02A61P35/00A61K2300/00
Inventor 袁卿姚亚文高学云
Owner BEIJING UNIV OF TECH
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