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Hypoxia-responsive chemically modified protein and its preparation method and application

A chemical modification and responsive technology, applied in the field of hypoxia-responsive protein modification and its preparation, can solve problems such as reducing non-specific effects of normal cells, and achieve the effects of reducing non-specific toxicity, protecting stability and restoring activity

Active Publication Date: 2021-09-28
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although protein drugs have many advantages in disease treatment, the protein itself is sensitive to different environmental conditions. Therefore, it is still a challenge to deliver therapeutic functional proteins to the target to exert their effects. Therapeutic proteins need to be introduced safely and effectively. To target cells, and minimize non-specific effects on normal cells. In the process, according to the characteristic physiological environment in diseased cells, the way of regulating protein activity, the development of protein functions, therapeutic methods and delivery process optimization very important

Method used

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  • Hypoxia-responsive chemically modified protein and its preparation method and application
  • Hypoxia-responsive chemically modified protein and its preparation method and application
  • Hypoxia-responsive chemically modified protein and its preparation method and application

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preparation example Construction

[0040] The preparation method of the hypoxia-responsive protein-modified polymer of the present invention is as follows:

[0041] 1) Preparation of activated monomethoxypolyethylene glycol: Dissolve monomethoxypolyethylene glycol in anhydrous toluene, and remove the solvent and water under reduced pressure; add anhydrous dichloromethane, triethylamine and p-toluenesulfonyl chloride, the mixture was stirred at room temperature for 5 to 8 hours; after continuing to add p-toluenesulfonyl chloride, stirred for 9 to 11 hours, and filtered off the insoluble matter; the filtrate was concentrated and separated by silica gel column chromatography to obtain activated monomethoxy poly Ethylene glycol, compound 1;

[0042] 2) Preparation of hydroxyazobenzene: Cool the suspension of p-aminobenzyl alcohol and water to 0-5 o C, and hydrochloric acid was added to the mixture; NaNO was added to the mixture at 0-5°C 2 Aqueous solution, and 0~5 o Stir at C for 1 hour; add the mixture of pheno...

Embodiment 1

[0059] A method for preparing an oxygen-responsive polymer, specifically as follows:

[0060] Preparation of activated monomethoxypolyethylene glycol: Dissolve monomethoxypolyethylene glycol (15 g, 15 mmol) in anhydrous toluene (100 mL) and remove the solvent under reduced pressure. The process was repeated twice to remove traces of water. Then anhydrous dichloromethane (DCM, 250 mL), triethylamine (14.5 mL, 105 mmol) and p-toluenesulfonyl chloride (20 g, 105 mmol) were added sequentially. The mixture was stirred at room temperature for 6 hours. After adding p-toluenesulfonyl chloride (20 g, 105 mmol), the stirring was continued for 10 hours, and the insoluble matter was filtered off. The filtrate was concentrated, and the obtained crude product was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid as activated monomethoxypolyethylene glycol (9.28 g, yield 48%), deuterated Chloroform NMR, with figure 1 its NMR spectrum....

Embodiment 2

[0065]

[0066] Use the hypoxia-responsive protein modification polymer synthesized in Example 1 to modify protein ribonuclease A (RNase), as follows:

[0067] To modify the primary amino group of lysine on protein RNase with azobenzene, dissolve RNase (5 mg) and compound 4 (5 mg) in NaHCO 3 solution (0.1 M, pH 8.5) and dimethyl sulfoxide (DMSO), the two were mixed and stirred at room temperature for 10 hours, after which the mixture was purified by ultrafiltration (MWCO = 3.5 kDa) and lyophilized (-80 °C), Obtain azobenzene-modified RNase (RPAB) for the following tests.

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Abstract

The invention discloses a hypoxia-responsive chemically modified protein and its preparation method and application. The activated monomethoxypolyethylene glycol and hydroxyazobenzene are mixed in the presence of a base and a catalyst, heated and stirred to react to obtain a monomethoxypolyethylene glycol The hydroxyazobenzene of ethylene glycol; then react the hydroxyazobenzene of monomethoxypolyethylene glycol with p-nitrophenyl chloroformate to obtain a hypoxia-responsive protein-modified polymer; under alkaline conditions , reacting the hypoxia-responsive protein modification polymer with the protein to obtain the hypoxia-responsive chemically modified protein. The hypoxia-responsive chemically modified protein prepared by the invention not only has excellent water solubility, but also does not change the secondary structure of the protein, and does not affect the performance of the protein after dissociation.

Description

technical field [0001] The present application relates to the field of chemical modification of proteins and polypeptides, and specifically relates to a hypoxia-responsive protein modification and its preparation method and application, which can regulate the activity of proteins and polypeptides before and after hypoxia. Background technique [0002] Proteins are the executors of biological functions, and have a variety of complex biological functions, such as catalyzing biochemical reactions, acting as receptors for intercellular material transport, and supporting skeletons between cells and so on. Theoretically, protein drugs can be used to treat almost all diseases with clear pathogenesis. Compared with small molecule drugs, protein drugs have incomparable advantages due to their high specificity, complex functionality and good biocompatibility. [0003] Although protein drugs have many advantages in disease treatment, the protein itself is sensitive to different enviro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K1/107A61K47/60A61K45/00A61P35/00C08G65/333
CPCA61K45/00A61K47/60A61P35/00C07K1/1077C08G65/33389C08G65/33396
Inventor 殷黎晨李旭东
Owner SUZHOU UNIV
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