Modified Saccharides Hydrolysis Resistance
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Solution Overview
Problem
Polysaccharides, particularly capsular polysaccharides, exhibit poor stability in water due to hydrolysis of O-glycosidic bonds, leading to fragmentation and yield loss in vaccine production, limiting the range of linkages that can be formed with carrier proteins and hindering the development of robust industrial-scale vaccine procedures.
Innovation Solution
Modification of hydroxyl groups on monosaccharide units with specific blocking groups, such as carbamate and ester groups, to enhance stability and retain immunological cross-reactivity, allowing for more stable saccharide-protein conjugates and improved vaccine production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If O-glycosidic bonds are used to join saccharide units, then the polysaccharide can be readily synthesized and manipulated, but the stability in water is poor due to hydrolysis
Solution Approach 1:
The patent changes the chemical parameter of the glycosidic bond from O-glycosidic to C-glycosidic, fundamentally altering the bond's resistance to hydrolysis while maintaining the polysaccharide's structural and functional properties. This parameter change resolves the contradiction by providing both stability and manufacturability.
Solution Approach 2:
The patent creates a composite structure where C-glycosidic bonds replace O-glycosidic bonds within the polysaccharide framework, combining the stability of carbon-carbon bonds with the biological functionality of saccharide structures. This composite approach maintains ease of manipulation while achieving water stability.
2Stability of the object's composition
If careful choice of reagents and conditions is made to prevent hydrolysis, then stability is improved, but the range of linkages that may be made with carrier protein is limited
Solution Approach 1:
The patent segments the polysaccharide structure into C-glycosidic backbone units that provide stability, while retaining terminal or side-chain functional groups (such as hydroxyl or carboxyl groups) that can be independently modified for protein conjugation. This segmentation allows stability in the main chain while preserving versatility in attachment options.
Solution Approach 2:
The patent applies different chemical qualities to different parts of the polysaccharide: the C-glycosidic bonds provide universal stability throughout the structure, while specific local functional groups at terminal positions or side chains provide localized sites for diverse protein linkages, thus maintaining both stability and adaptability.
3Stability of the object's composition
If C-glycosidic bonds are used to join saccharide units, then stability to hydrolysis is improved, but the complexity of synthesis may increase
Solution Approach 1:
The patent employs preliminary action by pre-synthesizing stable C-glycosyl donor units with defined stereochemistry and functional groups before assembling the polysaccharide chain. This preliminary preparation of building blocks simplifies the overall synthesis by modularizing the complex C-glycosidic bond formation process.
Solution Approach 2:
The patent uses chemical intermediaries such as activated C-glycosyl donors (e.g., glycosyl halides, glycosyl triflates, or glycosyl phosphates) that facilitate the formation of C-glycosidic bonds through well-established coupling reactions. These intermediaries mediate the complex bond formation, making the synthesis more manageable and less complex.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified saccharides demonstrate improved stability to hydrolysis while maintaining immunological properties, enabling a wider range of linkages and more robust vaccine production processes, particularly for conjugate vaccines like those against meningococcus.
Implementation Method 1
Poor stability in water is a result of the O-glycosidic bonds being readily hydrolysed in the presence of acids or glycosidases
Data Source
AI summary
Modified capsular saccharides comprising a blocking group at a hydroxyl group position on at least one of the monosaccharide units of the corresponding native capsular saccharide, wherein the blocking group is of the formula (Ia) or (Ib): —OX—Y (Ia) or —O—R1 (Ib) wherein X is C(O), S(O) or SO2; Y is NR1R2 or R3; R1 is C1-6 alkyl substituted with 1, 2 or 3 groups independently selected from hydroxyl, sulphydryl and amine; R2 is H or C1-6 alkyl; and R3 is C1-6 alkyl; processes for modifying a capsular saccharide with the blocking groups; saccharide-protein conjugates comprising the modified capsular saccharide; processes for making the saccharide-protein conjugates, pharmaceutical compositions comprising the modified capsular saccharides and/or saccharide-protein conjugates; and methods and uses of the same.