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Group A streptococcus oligosaccharide protein conjugate as well as preparation method and application thereof

A group A streptococcus and protein conjugate technology, applied in the direction of antibacterial drugs, pharmaceutical formulations, bacterial antigen components, etc., to achieve effective inhibition and good applicability

Inactive Publication Date: 2018-12-21
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the anti-group A streptococcal oligosaccharide conjugate vaccine is prepared by linking ScpA193 as a carrier with GAS oligosaccharide antigen, and there is no relevant literature report

Method used

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  • Group A streptococcus oligosaccharide protein conjugate as well as preparation method and application thereof
  • Group A streptococcus oligosaccharide protein conjugate as well as preparation method and application thereof
  • Group A streptococcus oligosaccharide protein conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: 3-aminopropyl α-L-rhamnopyranosyl-(1→2)-[2-deoxy-2-acetylamino-β-D-glucopyranosyl-(1→3) ]-α-L-rhamnopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[2-deoxy-2-acetylamino-β-D- Synthesis of Glucopyranosyl-(1→3)]-α-L-rhamnopyranose-ScpA193 Conjugate (N2-ScpA193)

[0043] 1. Synthesis of GAS oligosaccharide antigen N2

[0044] 1) Synthesis of Compound H1

[0045]

[0046] Under the protection of nitrogen, the compound 2-deoxy-2-phthalamido-3,4,6-triacetylglucopyranosamine trichloroacetimidate (2.52g, 4.35mmol) (Journal of Organic Chemistry 2005,70(1),214-226), 4-oxo-benzoylrhamnopyranosopropylglucoside (1.26g,4.14mmol)(CarbohydrateResearch.2011,346(17),2801-2804) 15mL of dry dichloromethane was dissolved and transferred to the activated In the molecular sieve reaction flask, add dry dichloromethane to 50 mL, stir at room temperature, after 30 minutes, add ice-water bath to cool down to 0°C, and add trimethylsilyl trifluoromethanesulfonate (79 μL, 0.435 mmol) d...

Embodiment 2

[0082] GAS oligosaccharide antigen N2 was synthesized according to the method described in Example 1.

[0083] A preparation method of group A streptococcal oligosaccharide protein conjugate N2-ScpA193, the steps are as follows:

[0084] (1) Activation of N2: Dissolve the GAS oligosaccharide antigen N2 (2 mg) prepared above in 1 mL of N,N-dimethylformamide (DMF) and phosphate buffered saline (PBS buffer, Na 2 HPO 4 0.1M, KH 2 PO 4 0.1M, pH 8) mixed solution (DMF:PBS=4:1, volume ratio), add disuccinimide glutarate to it under stirring condition, disuccinimide glutarate and GAS oligo The molar equivalent ratio of carbohydrate antigen N2 was 10:1, stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure to obtain a white powdery solid, which was washed with EA (ethyl acetate) and dried to obtain activated GAS oligosaccharide antigen N2;

[0085] (2) Synthesis of the conjugate: Dissolve the activated GAS oligosaccharide antigen N2 and...

Embodiment 3

[0089] Example 3: 3-aminopropyl α-L-rhamnopyranosyl-(1→2)-[2-deoxy-2-acetylamino-β-D-glucopyranosyl-(1→3) ]-α-L-rhamnopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[2-deoxy-2-acetylamino-β-D- Glucopyranosyl-(1→3)]-α-L-rhamnopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[2-deoxy -Synthesis of 2-acetylamino-β-D-glucopyranosyl-(1→3)]-α-L-rhamnopyranose-ScpA193 conjugate (N3-ScpA193)

[0090] 1. Synthesis of GAS oligosaccharide antigen N3

[0091] 1) Synthesis of Compound H10

[0092]

[0093] Under nitrogen protection, compound H4 (97mg, 0.126mmol) and compound H6 (161mg, 0.137mmol) prepared in Example 1 were transferred to an activated In a molecular sieve reaction vial, the solution was stirred at room temperature for 30 min. Then the temperature of the mixed solution was lowered to 0° C., and iodosuccinimide (42 mg, 0.187 mmol) and trimethylsilyl trifluoromethanesulfonate (3.4 μL, 18.7 μmol) were added. The reaction solution was stirred at 0°C for 1 hour and then slowly warme...

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Abstract

The invention relates to a group A streptococcus oligosaccharide protein conjugate as well as a preparation method and application thereof. In the group A streptococcus oligosaccharide protein conjugate, an oligosaccharide antigen is a clear and single oligomeric hexaose or nonaose derivative which can be synthesized according to a chemical method, a connecting arm is succinimide, and used novel carrier protein ScpA193 is a group A streptococcus virulence factor C5a peptidase deactivated through directional mutation. The invention further relates to the preparation method of the group A streptococcus oligosaccharide protein conjugate and application thereof to preparation of an anti-group A streptococcus vaccine. The group A streptococcus oligosaccharide protein conjugate can be simultaneously induced into two types of antibodies with different targets synergistically resisting group A streptococci, and is a composite vaccine. The vaccine has better applicability, can more effectivelyinhibit the group A streptococci, and is not limited by the bacterial resistance problem caused by large-scale use of antibiotics.

Description

technical field [0001] The invention relates to a group A streptococcal oligosaccharide protein conjugate, a preparation method and application thereof, and belongs to the technical field of anti-group A streptococcal vaccine development. Background technique [0002] Group A Streptococcus (GAS) is a common Gram-positive pathogen. According to statistics, the number of people who die from GAS infection diseases is about 500,000 in the world every year, and 80% of them are caused by GAS infection complications, mainly rheumatic diseases. Cardiac disease and aggressive GAS disease are the main ones (The Lancet Infectious Diseases 2005, 5(11), 685-694). For diseases caused by GAS infection, the common treatment method is the use of antibiotic intervention, but with the continuous enhancement of bacterial drug resistance, the development of anti-group A streptococcal vaccines is particularly important for the prevention and treatment of GAS infection diseases. [0003] An ideal...

Claims

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Application Information

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IPC IPC(8): A61K39/09A61K47/64A61P31/04
CPCA61K39/092A61K47/64A61P31/04
Inventor 顾国锋赵奕盛郭忠武王夙博李辉
Owner SHANDONG UNIV
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