CN112251484A - Method for preparing glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase - Google Patents
Method for preparing glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase Download PDFInfo
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Abstract
The invention discloses a method for preparing a glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase, belonging to the field of material science. According to the invention, a glycine oligopeptide is catalytically synthesized by using protease as a catalyst, then the glycine oligopeptide and polyethylene glycol monomethyl ether are polymerized under the catalysis of lipase, and polyethylene glycol is grafted on the tail end of oligoglycine to prepare the glycine oligopeptide-polyethylene glycol copolymer, wherein the lipase is any one of mucor javanicus lipase M, aspergillus niger lipase A, aspergillus oryzae lipase and thermomyces lanuginosus lipase. The yield of the glycine oligopeptide-polyethylene glycol copolymer reaches 45-75%. The catalyst in the synthesis step related to the method is enzyme, has the advantages of mild reaction conditions, more environment-friendly property, less side reaction and the like, and avoids the complicated protection and deprotection steps.
Description
Technical Field
The invention relates to a synthesis method of a glycine oligopeptide-polyethylene glycol copolymer, in particular to a method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase, belonging to the field of material science.
Background
The artificial polypeptide is a polyamino compound formed by taking natural amino acid as a monomer to carry out polymerization reaction through amido bond, and the properties of the artificial polypeptide are similar to those of natural peptide, polyamino acid and protein. The material formed by the artificial polypeptide has good biocompatibility and degradability. The polypeptide or the modified oligomer thereof shows unique structural properties such as self-assembly, liquid crystal behavior and the like, has stronger plasticity, and has great application potential in the fields of biology, medicine and natural high polymer materials. Pegylation can improve the water solubility and stability of peptides administered in vivo, and reduce immunogenicity. The pegylated peptides are capable of self-assembling to form various superstructures such as nanotubes, micelles, fibrils and organogels.
Examples of the polymerization method of amino acids include a solid phase method, an NCA method and an enzyme catalysis method. The methods for PEGylation of peptides include: an N-terminal modification method, a carboxyl modification method and a thiol modification method. Compared with a chemical reaction method, the enzyme catalysis method has the advantages of mild reaction conditions, more environment-friendly property, less side reaction and the like, and avoids fussy protection and deprotection steps.
Therefore, the search for a suitable method for synthesizing glycine oligopeptide and grafted polyethylene glycol thereof by enzyme catalysis has positive significance.
Disclosure of Invention
The invention aims to provide a method for preparing a glycine oligopeptide-polyethylene glycol copolymer by an enzyme method, which has mild reaction conditions and is more environment-friendly, aiming at the defects in the synthesis of the glycine oligopeptide-polyethylene glycol copolymer by a chemical method.
The first object of the invention is to provide a method for preparing a glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase, which comprises the following steps:
(1) synthesizing glycine oligopeptide under the catalysis of protease;
(2) catalyzing glycine oligopeptide to graft polyethylene glycol by using lipase to prepare a glycine oligopeptide-polyethylene glycol copolymer.
In one embodiment of the present invention, in step (1), the method for synthesizing glycine oligopeptide by protease catalysis comprises: adding L-glycine methyl ester hydrochloride, dimethyl sulfoxide and protease into a phosphate buffer solution, and reacting for 5-10 hours at 30-70 ℃; and after the reaction is finished, centrifuging to obtain a precipitate, washing, and freeze-drying to obtain the glycine oligopeptide.
In one embodiment of the present invention, in the step (1), the protease includes any one of bromelain, papain, trypsin, neutral protease and alkaline protease, and the amount of the protease added is 1 to 10U/g L-glycine methyl ester hydrochloride.
In one embodiment of the present invention, in the step (1), the phosphate buffer is 0.1 to 0.2M disodium hydrogen phosphate-citric acid buffer, and the pH of the phosphate buffer is 5.5 to 8.0.
In one embodiment of the invention, the mass-to-volume-per-mL ratio of the L-glycine methyl ester hydrochloride to the phosphate buffer is 1: 1-6.
In one embodiment of the present invention, in the step (1), the volume of the dimethyl sulfoxide is 2.5 to 25% of the volume of the phosphate buffer.
In one embodiment of the invention, the reaction mixture is reacted in a constant temperature shaker (600 rpm).
In one embodiment of the present invention, the centrifugation is centrifugation of the reaction mixture at 5000 to 10000rpm for 2 to 6 min.
In one embodiment of the present invention, the washing is performed 2 to 4 times with water and glacial ethanol, respectively.
In one embodiment of the present invention, in the step (2), the method for preparing the glycine oligopeptide-polyethylene glycol copolymer by catalyzing the glycine oligopeptide to graft polyethylene glycol by using the lipase comprises the following steps:
adding the glycine oligopeptide prepared in the step (1), polyethylene glycol monomethyl ether and lipase into anhydrous trichloroethane, and reacting for 10-24 hours at an absolute pressure of 0-101.325 KPa and a temperature of 30-50 ℃; and after the reaction is finished, standing the reaction mixture at-4-0 ℃ for 8-20 h, carrying out vacuum filtration, drying the filtrate, adding preheated acetone, stirring until the acetone is completely dissolved, standing the obtained solution at-4-0 ℃ for 8-20 h, and carrying out vacuum filtration to obtain a precipitate, namely the glycine oligopeptide-polyethylene glycol copolymer.
In one embodiment of the invention, the mass g volume mL of the glycine oligopeptide, the methoxypolyethylene glycol and the anhydrous trichloroethane is 1: 1.2-3, and the weight ratio of the glycine oligopeptide, the methoxypolyethylene glycol is 1: 1.2-1: 5.
In one embodiment of the invention, the polyethylene glycol monomethyl ether has an average molecular weight of 200, 400 or 1000 Da.
In one embodiment of the invention, the addition amount of the lipase is 1-10U/g substrate, and the substrate is glycine oligopeptide and polyethylene glycol monomethyl ether.
In one embodiment of the present invention, the lipase is any one of mucor javanicus lipase M, aspergillus niger lipase a, aspergillus oryzae lipase, and thermomyces lanuginosus lipase.
In one embodiment of the present invention, the reaction is carried out under stirring at a speed of 100 to 500 rpm.
In one embodiment of the present invention, the drying is preferably vacuum drying, and the operating parameters are: vacuum drying for 4-12 hours at 30-60 ℃.
In one embodiment of the present invention, the yield of the glycine oligopeptide-polyethylene glycol copolymer is 45-75%.
In one embodiment of the invention, by1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer detected by an H NMR method is 1.01-1.1.
In one embodiment of the present invention,1the detection method of HNMR is as follows: using AVANCE III HD-400MHz NMR spectrometer with CF3With COOD as solvent and Tetramethylsilane (TMS) as internal standard, and the copolymers are measured at room temperature1H NMR spectrum.
The second purpose of the invention is to provide the application of the preparation method in the fields of biology, medicine and natural polymer materials.
Compared with the prior art, the invention mainly has the following advantages:
the glycine oligopeptide is synthesized by an enzyme catalysis method, the condition is mild, no pollution is caused, and the yield is as high as 50-70%. Compared with a chemical method, the glycine oligopeptide-polyethylene glycol copolymer is synthesized by lipase catalysis, the method has the advantages of mild conditions, more environment-friendly property and less side reaction, avoids fussy protection and deprotection steps, and has a yield of 45-75%.
Detailed Description
The present invention is further described below with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1
(1) Protease catalyzed synthesis of glycine oligopeptide
To 2.0mL of disodium hydrogenphosphate-citric acid buffer (manufactured by Nanchang rain and dew laboratory Co., Ltd.) at pH5.8, 0.5g of L-glycine methyl ester hydrochloride (national pharmaceutical group chemical Co., Ltd.), dimethyl sulfoxide (national pharmaceutical group chemical Co., Ltd.) and 2U of trypsin (Shanghai Vocko Biotechnology Co., Ltd.) were added. The volume fraction of dimethyl sulfoxide was 2.5% phosphate buffer. The reaction mixture was placed in a constant temperature shaker (600rpm) and reacted at 30 ℃ for 10 hours. After the reaction is finished, the reaction mixture is centrifuged for 3 minutes at 10000rpm, precipitates are washed twice by deionized water and glacial ethanol respectively, and the glycine oligopeptide product is obtained after freeze drying.
(2) Preparation of Glycine oligopeptide-polyethylene glycol copolymer
5g of glycine oligopeptide, polyethylene glycol monomethyl ether 200 (national pharmaceutical group chemical Co., Ltd.) and 10U of Mucor javanicus lipase M (Shanghai Albantin Biotechnology Co., Ltd.) were added to 15ml of anhydrous trichloroethane (national pharmaceutical group chemical Co., Ltd.). The weight ratio of the glycine-alanine oligopeptide to the polyethylene glycol monomethyl ether is 1: 1.2. The reaction mixture was stirred (200rpm) at 50 ℃ for 10h at an absolute pressure of 10.1 KPa. After completion of the reaction, the reaction mixture was allowed to stand at 0 ℃ overnight, and suction filtration was carried out under reduced pressure. After drying the filtrate in vacuum at 30 ℃ for 6 hours, acetone preheated to 40 ℃ was added and stirred until all dissolved. Standing the obtained solution at 0 ℃ overnight, and performing suction filtration under reduced pressure to obtain a precipitate of glycine oligopeptide-polyethylene glycol copolymer with a yield of 45%. By passing1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer detected by an H NMR method is 1.01.
Example 2
(1) Protease catalyzed synthesis of tyrosine oligopeptide
To 2.5mL of disodium hydrogenphosphate-citric acid buffer (manufactured by Nanchang rain dew laboratory instruments Co., Ltd.) at pH7.0, 0.15M, 1g of L-glycine methyl ester hydrochloride (national pharmaceutical group chemical reagent Co., Ltd.), dimethyl sulfoxide (national pharmaceutical group chemical reagent Co., Ltd.) and 3.5U of papain (Shanghai Vocko Biotechnology Co., Ltd.) were added. The volume fraction of dimethyl sulfoxide was 15% phosphate buffer. The reaction mixture was placed in a constant temperature shaker (600rpm) and reacted at 30 ℃ for 8 hours. After the reaction is finished, the reaction mixture is centrifuged for 3 minutes at 10000rpm, precipitates are washed twice by deionized water and glacial ethanol respectively, and the glycine oligopeptide product is obtained after freeze drying.
(2) Preparation of Glycine oligopeptide-polyethylene glycol copolymer
To 12ml of anhydrous trichloroethane (national pharmaceutical group chemical Co., Ltd.) were added 8g of glycine oligopeptide, polyethylene glycol monomethyl ether 400 (national pharmaceutical group chemical Co., Ltd.), and 20U of Aspergillus oryzae lipase (Shanghai Allan Biotech Co., Ltd.). The weight ratio of the glycine-alanine oligopeptide to the polyethylene glycol monomethyl ether is 1: 1.5. The reaction mixture was stirred (200rpm) at an absolute pressure of 101.325KPa and 40 ℃ for 14 h. After the reaction was completed, the reaction mixture was allowed to stand at 0 ℃ for 10 hours, and suction filtration was performed under reduced pressure. After drying the filtrate in vacuum at 30 ℃ for 6 hours, acetone preheated to 40 ℃ was added and stirred until all dissolved. And standing the obtained solution at-1 ℃ for 12 hours, and performing vacuum filtration to obtain a precipitate which is a glycine oligopeptide-polyethylene glycol copolymer with the yield of 65%. By passing1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer detected by an H NMR method is 1.0.
Example 3
(1) Protease catalyzed synthesis of tyrosine oligopeptide
To 2.5mL of a disodium hydrogenphosphate-citric acid buffer (manufactured by Nanchang Yulu laboratory instruments Co., Ltd.) and 0.2M, pH 8.0.0, 1g of L-glycine methyl ester hydrochloride (national pharmaceutical group chemical Co., Ltd.), dimethyl sulfoxide (national pharmaceutical group chemical Co., Ltd.) and 3.5U of alkaline protease (Shanghai Vocko Biotechnology Co., Ltd.) were added. The volume fraction of dimethyl sulfoxide was 25% phosphate buffer. The reaction mixture was placed in a constant temperature shaker (600rpm) and reacted at 70 ℃ for 5 hours. After the reaction is finished, the reaction mixture is centrifuged for 3 minutes at 10000rpm, precipitates are washed twice by deionized water and glacial ethanol respectively, and the glycine oligopeptide product is obtained after freeze drying.
(2) Preparation of Glycine oligopeptide-polyethylene glycol copolymer
To 14ml of anhydrous trichloroethane (national chemical group Co., Ltd.) were added 10g of glycine oligopeptide, polyethylene glycol monomethyl ether 1000 (national chemical group Co., Ltd.), and 50U of Thermomyces lanuginosus lipase (Shanghai Aladdin Biotech Co., Ltd.). The weight ratio of the glycine-alanine oligopeptide to the polyethylene glycol monomethyl ether is 1: 1.2. The reaction mixture was stirred (200rpm) at 50 ℃ under an absolute pressure of 50.5KPa for 24 h. After the reaction was completed, the reaction mixture was allowed to stand at-4 ℃ for 20 hours, and suction filtration was carried out under reduced pressure. After drying the filtrate in vacuum at 30 ℃ for 6 hours, acetone preheated to 40 ℃ was added and stirred until all dissolved. And standing the obtained solution at 0 ℃ for 8 hours, and performing suction filtration under reduced pressure to obtain a precipitate, namely the glycine oligopeptide-polyethylene glycol copolymer, wherein the yield is 75%. By passing1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer detected by an H NMR method is 1.0.
Example 4
(1) Protease catalyzed synthesis of tyrosine oligopeptide
To 5mL of 0.1M, pH 7.0.0 disodium hydrogen phosphate-citric acid buffer (manufactured by Nanchang rain and dew laboratory Co., Ltd.) were added 2g of L-glycine methyl ester hydrochloride (national pharmaceutical group chemical Co., Ltd.), dimethyl sulfoxide (national pharmaceutical group chemical Co., Ltd.) and 5U of alkaline protease (Shanghai Wakai Biotech Co., Ltd.). The volume fraction of dimethyl sulfoxide was 15% phosphate buffer. The reaction mixture was placed in a constant temperature shaker (600rpm) and reacted at 50 ℃ for 5 hours. After the reaction is finished, the reaction mixture is centrifuged for 3 minutes at 10000rpm, precipitates are washed twice by deionized water and glacial ethanol respectively, and the glycine oligopeptide product is obtained after freeze drying.
(2) Preparation of Glycine oligopeptide-polyethylene glycol copolymer
To 10ml of anhydrous trichloroethane (national pharmaceutical group chemical Co., Ltd.) were added 8g of glycine oligopeptide, polyethylene glycol monomethyl ether 1000 (national pharmaceutical group chemical Co., Ltd.), and 30U of Aspergillus niger lipase A (Shanghai Allan Biotechnology Ltd.). The weight ratio of the glycine-alanine oligopeptide to the polyethylene glycol monomethyl ether is 1: 1.15. The reaction mixture was stirred (200rpm) at 40 ℃ for 20h at an absolute pressure of 50.5 KPa. After the reaction was completed, the reaction mixture was allowed to stand at 0 ℃ for 8 hours, and suction filtration was performed under reduced pressure. After drying the filtrate in vacuum at 30 ℃ for 10 hours, acetone preheated to 40 ℃ was added and stirred until all dissolved. And standing the obtained solution at 0 ℃ for 20 hours, and performing suction filtration under reduced pressure to obtain a precipitate which is a glycine oligopeptide-polyethylene glycol copolymer, wherein the yield is 65%. By passing1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer detected by an H NMR method is 1.05.
Comparative example 1
When other common lipase such as lipase B of Candida antarctica is used in step (2) of example 1, other operation steps and parameters are the same as those in example 1. After the reaction was complete, the yield of product was only 12%. By passing1The substitution degree of the glycine oligopeptide-polyethylene glycol copolymer is detected by an H NMR method and is 1.
Comparative example 2
When the solvent in step (2) of example 1 was absolute ethanol (not trichloroethane), the remaining operational steps and parameters were the same as in example 1, and after completion of the reaction, the reaction mixture was allowed to stand at 0 ℃ for 20 hours and suction-filtered under reduced pressure. After the filtrate was dried under vacuum at 30 ℃ for 6 hours, no glycine oligopeptide-polyethylene glycol copolymer was detected.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A method for preparing a glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase, which is characterized by comprising the following steps:
(1) synthesizing glycine oligopeptide under the catalysis of protease;
(2) and catalyzing glycine oligopeptide with polyethylene glycol by using lipase to prepare the glycine oligopeptide-polyethylene glycol copolymer.
2. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase according to claim 1, wherein in the step (1), the method for synthesizing the glycine oligopeptide under the catalysis of protease comprises the following steps: adding L-glycine methyl ester hydrochloride, dimethyl sulfoxide and protease into a phosphate buffer solution, and reacting for 5-10 hours at 30-70 ℃; after the reaction is finished, centrifuging to take precipitate, washing, freezing and drying to obtain the glycine oligopeptide.
3. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase according to claim 2, wherein the protease comprises any one of bromelain, papain, trypsin, neutral protease and alkaline protease, and the addition amount of the protease is 1-10U/g L-glycine methyl ester hydrochloride.
4. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of the lipase as claimed in claim 2 or 3, wherein the phosphate buffer is 0.1-0.2M disodium hydrogen phosphate-citric acid buffer, the pH value of the phosphate buffer is 5.5-8.0, and the volume of the dimethyl sulfoxide is 2.5-25% of the phosphate buffer.
5. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase according to any one of claims 1 to 4, wherein in the step (2), the method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of the lipase for grafting the glycine oligopeptide with polyethylene glycol comprises the following steps:
adding the glycine oligopeptide prepared in the step (1), polyethylene glycol monomethyl ether and lipase into anhydrous trichloroethane, and reacting for 10-24 hours at an absolute pressure of 0-101.325 KPa and a temperature of 30-50 ℃; and after the reaction is finished, standing the reaction mixture at-4-0 ℃ for 8-20 h, carrying out vacuum filtration, drying the filtrate, adding preheated acetone, stirring until the acetone is completely dissolved, standing the obtained solution at-4-0 ℃ for 8-20 h, and carrying out vacuum filtration to obtain a precipitate, namely the glycine oligopeptide-polyethylene glycol copolymer.
6. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase as claimed in claim 5, wherein the mass g volume mL of the glycine oligopeptide, the polyethylene glycol monomethyl ether and the anhydrous trichloroethane is 1: 1.2-3, and the weight ratio of the glycine oligopeptide, the polyethylene glycol monomethyl ether is 1: 1.2-1: 5.
7. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase as claimed in claim 5 or 6, wherein the average molecular weight of the polyethylene glycol monomethyl ether is 200, 400 or 1000 Da.
8. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of the lipase as claimed in any one of claims 5 to 7, wherein the addition amount of the lipase is 1-10U/g of substrate, and the substrate is glycine oligopeptide and polyethylene glycol monomethyl ether.
9. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of lipase according to any one of claims 1 to 8, wherein the lipase is any one of Mucor javanicus lipase M, Aspergillus niger lipase A, Aspergillus oryzae lipase and Thermomyces lanuginosus lipase.
10. The method for preparing the glycine oligopeptide-polyethylene glycol copolymer under the catalysis of the lipase as claimed in any one of claims 1 to 9, and the application of the method in the fields of biology, medicine and natural high polymer materials.
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