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Polyglycols modified disinfection/neutralization endotoxin polypeptide, preparation and uses thereof

A technology of polyethylene glycols and polyethylene glycols, applied in the field of polypeptides

Inactive Publication Date: 2009-04-08
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research on PEG modification of synthetic small molecule peptides started late, but it has attracted the attention of many researchers

Method used

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  • Polyglycols modified disinfection/neutralization endotoxin polypeptide, preparation and uses thereof
  • Polyglycols modified disinfection/neutralization endotoxin polypeptide, preparation and uses thereof
  • Polyglycols modified disinfection/neutralization endotoxin polypeptide, preparation and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, mPEG-NHCOCH 2 CH 2 Preparation of CO-BNEP-OH (solid-phase stepwise synthesis)

[0061] 1. mPEG-NH 2 preparation of

[0062] (1) Preparation of mPEG-OTs

[0063] Weigh 18.000g (3mmol) mPEG (molecular weight 6000), add 45mL DCM to dissolve it, then add 14.958g (75mmol) p-toluenesulfonyl chloride (TsOCl) and 6mL Py, stir the reaction at room temperature under nitrogen protection, and use a thin Layer chromatography (TLC) monitors the progress of the reaction, stops the reaction after 40 hours, and distills under reduced pressure at a temperature of 32°C to 1 / 3 of the original volume, then continues to stir the reaction at room temperature and under nitrogen protection conditions for 3 hours, and then Distill under reduced pressure at 32°C until no liquid distills out, add 150mL ice diethyl ether (that is, diethyl ether pre-cooled to a temperature of 4°C) in an ice bath and vigorously stir, stir for 10 minutes, and stand at a temperature of 4°C for 1 hour...

Embodiment 2

[0085] Embodiment 2, H-BNEP (1-COCH 2 CH 2 Preparation of CONH-mPEG)-OH (solid-phase stepwise synthesis)

[0086] 1. mPEG-NH 2 preparation of

[0087] (1) Preparation of mPEG-OTs

[0088] Weigh 18.000g (3mmol) mPEG (molecular weight 6000), add 150mL tetrahydrofuran (THF), stir to dissolve it, then add 3mL THF solution of sodium naphthalene with a concentration of 1mol / L, and pass nitrogen gas at room temperature for 30 minutes under stirring conditions , add 0.686g (3.6mmol) TsOCl again, stir reaction under nitrogen protection condition, monitor reaction progress with TLC method, stop reaction after 5 hours, suction filtration, add 100mL glacial ether to filtrate under stirring condition, stir 10 minutes, in Stand at 4°C for 1 hour, filter with suction, wash the filter residue with glacial ether, recrystallize with EtOH, and place in P 2 o 5 Vacuum-dried in a vacuum desiccator to obtain white powdery solid 16.605g, yield 89.9%, IR and 1 HNMR identified as mPEG-OTs;

[...

Embodiment 3

[0121] Embodiment 3, H-BNEP (3-COCH 2 CH 2 Preparation of CONH-mPEG)-OH (solid-phase stepwise synthesis)

[0122] Prepare with reference to the method described in Example 2:

[0123] pre-made Then with Fmoc-Lys (COCH 2 CH 2 Prepared by coupling CONH-mPEG)-OH Then continue to couple with Fmoc-AA-OH step by step, and finally remove the Fmoc protecting group of the amino group to obtain Will Cleavage reaction with TFA-PhSMe-TES-PhOMe mixed solution with a volume ratio of 90:5:3:2 to obtain H-BNEP (3-COCH 2 CH 2 CONH-mPEG)-OH.

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Abstract

The invention discloses a sterilization / endotoxin neutralization polypeptide modified by polyethylene glycol, which consists of a formula as follows: X-Y-BNEP-OH or H-BNEP(i-Y-X)-OH, wherein, X is polyethylene glycol or single-methoxy polyethylene glycol, Y is a linking group, i is 1 or 3 or 13 or 14, representing the position number of lysine with a modified on side-chain amino group in an amino acid sequence; and BNEP is the sterilization / endotoxin neutralization polypeptide which has an amino acid sequence shown by SEQ ID No.1; the modification polypeptide, while maintaining the endotoxin neutralization activity of BNEP, prolongs the half-life in vivo of BNEP, and shows potential for being developed into new endotoxin neutralization medicaments, thus being capable of providing new curative medicaments for treating patients of severe diseases such as pyaemia, septic shock and the like. The invention also discloses a preparation method of the modification polypeptide, which has high product yield and high purity, thus being capable of realizing fixed-point modification of polyethylene glycol of synthetic polypeptide.

Description

technical field [0001] The invention relates to a polypeptide, in particular to a bactericidal / neutralizing endotoxin polypeptide modified by polyethylene glycols, and also relates to a preparation method and application of the modified polypeptide. Background technique [0002] Sepsis is Gram-negative (G - ) bacterial infection caused by systemic inflammatory response syndrome (systemic inflammatory response syndrome, SIRS) is one of the serious complications of severe trauma, extensive burns and other clinical critically ill patients, and is also the cause of septic shock (septic shock), An important cause of multiple organ dysfunction syndrome (MODS). According to the statistical survey results of the Centers for Disease Control and Prevention in the United States, about 750,000 people are infected with sepsis every year in the United States, and more than 210,000 people die because of it. It has been proved that the existence of G - The endotoxin (lipopolysaccha-rides...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/107C07K1/06C07K1/04A61K38/10A61P31/00
Inventor 杨大成范莉李同金田茂奎孔令强唐雪梅周祖文陈力
Owner SOUTHWEST UNIV
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