Beta-1,2-D-oligomeric mannose peptide-protein conjugate and preparation method and application thereof

A protein conjugate and mannopeptide technology, which is applied in the field of beta-1,2-D-oligomannosyl peptide-protein conjugate and its preparation, can solve problems such as limited immune response, and achieve strong application value Effect

Inactive Publication Date: 2017-02-01
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, through research, we found that there are certain deficiencies in the design of the above-mentioned vaccines: only the cell surface protein or the

Method used

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  • Beta-1,2-D-oligomeric mannose peptide-protein conjugate and preparation method and application thereof
  • Beta-1,2-D-oligomeric mannose peptide-protein conjugate and preparation method and application thereof
  • Beta-1,2-D-oligomeric mannose peptide-protein conjugate and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The synthesis of embodiment 1 compound 5

[0060] Monosaccharide acceptor 3 (1.23g, 2.5mmol) (J.Org.Chem.2001, 66, 8411.), donor 4 (1.95g, 3.0mmol) (J.Carbohydr.Chem.1994, 13, 421.) and activated Molecular sieves (1.0 g) were placed in a 100 mL round bottom flask and dried under vacuum for half an hour, then the mixture was dissolved in 50 mL of anhydrous dichloromethane. The suspension was stirred at room temperature under argon protection for half an hour, then cooled to -40°C, and then trimethylsilyl triflate (35.0 μL, 0.18 mmol) was slowly added dropwise. After half an hour, the reaction solution was neutralized and quenched with triethylamine and filtered with diatomaceous earth. After concentration, the initial product obtained was subjected to silica gel column chromatography (n-hexane / ethyl acetate, 12:1, v / v) to obtain a white foamy solid (2.23g, 92.4%).

[0061] 1 HNMR (400MHz, CDCl 3 )δ7.40-7.19(m,30H,Ar),5.88(m,1H,OCH 2 C H =CH 2 ),5.37(m,1H,OCH 2 ...

Embodiment 2

[0062] The synthesis of embodiment 2 compound 6

[0063] Compound 5 (1.85g, 2.0mmol) was dissolved in 100mL of anhydrous methanol, sodium methoxide (11.0mg, 0.2mmol) was added and stirred at room temperature overnight, after the reaction was completed, it was added to ion exchange resin IR 120 (H+form) And, the resin was removed by filtration, and the initial product obtained after concentration was subjected to silica gel column chromatography (n-hexane / ethyl acetate, 4:1, v / v) to obtain a white foamy solid (1.74g, 94.2%).

[0064] 1 H NMR (400MHz, CDCl 3 )δ7.55-7.23(m,30H,Ar),6.05-5.93(m,1H,OCH 2 C H =CH 2 ),5.40(m,1H,OCH 2 CH=C H 2 ),5.29(m,1H,OCH 2 CH=C H 2 ), 5.17 (dd, J=11.2Hz, 1H, OCH 2 Ph),5.05-4.93(m,4H,OCH 2 Ph), 4.90 (d, J=11.2Hz, 1H, OCH 2 Ph), 4.81(d, J=7.6Hz, 1H, H-1'), 4.72(d, J=12.0Hz, 1H, OCH 2 Ph),4.67-4.46(m,10H,OCH 2 Ph,O CH 2 CH=CH 2 ,H-1), 4.36(d,J=3.2Hz,1H,H-2),4.17-4.10(m,1H,O CH 2 CH=CH 2 ),4.01(t,J=9.6Hz,1H,H-4),3.88-3.71(m,6H,H...

Embodiment 3

[0065] The synthesis of embodiment 3 compound 7

[0066] Compound 6 (1.38 g, 1.5 mmol) was placed in a 100 mL round bottom flask, and then dimethyl sulfoxide (22.0 mL) and acetic anhydride (11.0 mL) were added. The reaction solution was stirred at room temperature for 18 hours, extracted with ethyl acetate, washed with saturated sodium carbonate and brine respectively, then dried with anhydrous sodium sulfate, filtered and concentrated to obtain the initial product, which was spun twice with toluene. The residue was dissolved in 40 mL of anhydrous tetrahydrofuran and cooled to -78°C, and L-Selectride (1 M THF, 7.5mL) and stirred for fifteen minutes, then removed the cooling device and placed at room temperature to continue stirring for fifteen minutes, quenched the reaction with methanol and diluted with 50mL dichloromethane, and the solutions were diluted with hydrogen peroxide solution (5%, 30mL), sodium hydroxide solution (1 M , 30mL), sodium thiosulfate solution (5%, 30...

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Abstract

The invention discloses a beta-1,2-D-oligomeric mannose peptide-protein conjugate shown in the formula I and a preparation method and application thereof. In the formula, n is 0 or 1 or 2, and R is carrier protein KLH or HSA. Alpha-D-glucose and alanine resin serve as raw materials, beta-1,2-D-oligomeric mannose peptide is synthesized, the beta-1,2-D-oligomeric mannose peptide is coupled with the carrier protein, and the corresponding beta-1,2-D-oligomeric mannose peptide-protein conjugate is obtained. The prepared compound serves as an anti-candida albicans vaccine to immunize mice, the result shows that the compound can induce the organism to generate high immune response, immunogenicity of the beta-1,2-D-oligomeric mannose peptide-protein conjugate is highest, generated immune serum can be bonded with a candida albicans cell surface antigen, therefore, the effect of resisting candida albicans infection can be achieved, and the beta-1,2-D-oligomeric mannose peptide-protein conjugate has high application value.

Description

technical field [0001] The present invention relates to the technical field of antifungal glycopeptide vaccines, in particular to a β-1,2-D-oligomannosyl peptide-protein conjugate and a preparation method thereof. The glycopeptide-protein conjugate The application of the drug as a vaccine in the prevention and treatment of Candida albicans infection. Background technique [0002] At this stage, the clinical fungal infection caused by Candida albicans is on the rise, and the bacteria have developed serious drug resistance to antibiotics. Research on new anti-Candida albicans fungal vaccines undoubtedly provides a good treatment method and strategy. At present, the research targets of such vaccines mainly focus on the functional proteins and polysaccharides on the cell surface of Candida albicans. Studies have found that various types of proteins contained in the cell wall of Candida albicans are closely related to the functions of fungal invasion, adhesion and phagocytosis, ...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/107A61K39/00A61P31/10
CPCC07K9/00A61K39/0002
Inventor 潘炜华潘搏廖俊廖万清桑军军李颖芳
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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