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Oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide, preparation method and applications thereof

A technology of Streptococcus pneumoniae and capsular polysaccharides, which is applied in the direction of medical preparations containing active ingredients, antibacterial drugs, drug combinations, etc., can solve problems such as poor biocompatibility, unpredictable impact of biological activity, and different effects. To achieve the effect of promoting antibody maturation

Active Publication Date: 2017-10-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of conjugate vaccine has several disadvantages: (1) the capsular polysaccharide obtained by crushing the bacteria is not a single substance, and the length of the capsular polysaccharide sugar chain is different; (2) it is inevitable in the process of extracting the capsular polysaccharide (3) The effect of each batch of conjugated vaccines may be different, with microscopic inhomogeneity, and the product quality is difficult to control
However, since the carrier molecule is a type of small molecular compound - glycosphingolipids, its biocompatibility is poor, and the duration of immune memory is short; and currently no immunogenic biomacromolecule and Streptococcus pneumoniae cell surface Linkage of oligomeric derivatives of type 3 capsular polysaccharides, such as diphtheria toxoid CRM197, tetanus toxoid (TT), and monophosphorylated lipid A, etc.
The main technical problem is that the oligomeric derivatives of type 3 capsular polysaccharides on the cell surface of Streptococcus pneumoniae are linked to different immunogenic biomacromolecules, and the impact on their biological activities is unpredictable

Method used

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  • Oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide, preparation method and applications thereof
  • Oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide, preparation method and applications thereof
  • Oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: general synthetic method

[0043] A: Benzoylation reaction

[0044] Get the raw material (1 mass part) and dissolve in pyridine, add benzoyl chloride solution (2.2 mass parts) under stirring condition, stir at room temperature for 2 hours, as the reaction proceeds, white solid is constantly separated out, concentrated, recrystallized, Filter to obtain a white solid product;

[0045] B: 4,6-position benzylidene transposition reaction

[0046] Take raw material (1 gram) and dissolve in dry 15 milliliters of dichloromethane, under the conditions of 0 ℃ and nitrogen protection, add triethylsilane (5 mass parts) and trifluoroacetic acid (5 mass parts), stir reaction 2 After 1 hour, dilute the reaction solution with 20 ml of dichloromethane, wash and extract with saturated aqueous sodium bicarbonate solution 3 times, take the lower organic phase, dry with anhydrous sodium sulfate, filter, concentrate, and separate with silica gel column chromatography. Deliqu...

Embodiment 2

[0056] Example 2: 3-aminopropyl β-D-glucosyl-(1→3)-β-D-glucosyl-(1→4)-β-D-glucosyl-(1→3)-β Synthesis of -D-glucosyl acid-(1→4)-β-D-glucose-TT conjugate (A17-TT)

[0057] (1) Synthesis of p-tolylthio 2,3,4,6-tetra-oxo-acetyl-1-thio-β-D-glucose (A1)

[0058]

[0059] Take β-D-full acetyl sugar (10.0g, 25.6mmol) and p-cresol (3.8g, 30.6mmol), after drying, dissolve in 50mL of dry dichloromethane, and add 10mL of Boron trifluoride ether solution, react at room temperature for 3 to 4 hours, TLC (PE:EA=1:2) to detect the reaction situation, until the raw materials no longer decrease, dilute the reaction solution with an appropriate amount of dichloromethane, and dilute the reaction solution with saturated NaHCO 3 After the aqueous solution was washed and extracted 3 times, the organic phase of the lower layer was removed and washed with anhydrous Na 2 SO 4 Dry, filter, concentrate, and separate by silica gel column chromatography to obtain compound A1 (10.0 g, yield 86%).

[...

Embodiment 3

[0112] Example 3: 3-Aminopropyl β-D-glucosyl-(1→4)-β-D-glucosyl-(1→3)-β-D-glucosyl-(1→4)- Synthesis of β-D-glucosyl-(1→3)-β-D-glucosyl-(1→4)-β-D-glucose-TT conjugate (B5-TT)

[0113] (1) 3-Azidopropyl 2,3-di-oxo-benzoyl-4,6-oxo-benzylidene-β-D-glucosyl-(1→4)-2,3-di- Synthesis of Oxy-benzoyl-6-oxo-benzyl-1-thio-β-D-glucose (B1)

[0114]

[0115] Using A4 (634.2 mg, 1.09 mmol) as the glycosyl donor and A5 (511.9 mg, 0.88 mmol) as the glycosyl acceptor, the target product B1 (676 mg, Yield 74%).

[0116] (2) 3-Azidopropyl 2,3-di-benzoyl-4,6-oxo-benzylidene-β-D-glucosyl-(1→4)-2,3-di-benzoyl Acyl-6-oxo-benzyl-β-D-glucosyl-(1→3)-2-oxo-benzoyl-4,6-oxo-benzylidene-β-D-glucosyl-(1→4 )-2,3-di-oxo-benzoyl-6-oxo-benzyl-β-D-glucosyl-(1→3)-2-oxo-benzoyl-4,6-oxo-benzyl Synthesis of -β-D-glucosyl-(1→4)-2,3-di-oxo-benzoyl-6-oxo-benzyl-1-thio-β-D-glucose (B2)

[0117]

[0118] Take B1 (355.6mg, 0.34mmol) as the glycosyl donor, A13 (491.9mg, 0.28mmol) as the glycosyl acceptor, carry ...

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Abstract

The present invention relates to an oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide, a preparation method and applications thereof, wherein the structure general formula of the oligosaccharide conjugate is defined in the specification. According to the present invention, the system of the Streptococcus pneumoniae type 3 capsular polysaccharide related oligosaccharide derivative is firstly discloses, and can be used for preparing a novel oligosaccharide-protein binding vaccine against Streptococcus pneumoniae type 3.

Description

technical field [0001] The invention relates to an oligosaccharide conjugate based on Streptococcus pneumoniae type 3 capsular polysaccharide and its preparation method and application, belonging to the technical field of Streptococcus pneumoniae vaccine development. Background technique [0002] Streptococcus pneumoniae is a Gram-positive diplococcus first isolated in 1881 by both US Army physician George Sternberg and French chemist Louis Pasteur. It often lives in the nasopharyngeal cavity of people, and can cause respiratory tract infection and lung infection. In severe cases, it can cause diseases such as meningitis, otitis media, and sepsis. Nearly 1 million children under the age of 5 die from these diseases every year in developing countries, and the prevention and treatment of these infectious diseases requires a lot of financial resources. [0003] There is a thick layer of sugar coating on the surface of Streptococcus pneumoniae, which can reduce the influence of...

Claims

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Application Information

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IPC IPC(8): A61K39/09A61K39/385A61P31/04A61P11/00
CPCA61K39/092A61K39/385A61K2039/575A61K2039/6018A61K2039/6037A61K2039/6081A61K2039/627
Inventor 顾国锋熊成鹤郭忠武冯少杰乔银
Owner SHANDONG UNIV
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