Thio-ether linked oligosaccharides for stable glycoconjugate vaccines
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Glycoconjugate vaccines face challenges in stabilizing antibody responses against specific glycans, as mannosidase trimming degrades the Manα1→2Man moieties of high mannose glycans, directing the immune response towards the glycan core rather than the extremities, which reduces their effectiveness.
Innovation Solution
Development of oligosaccharides with two saccharide moieties coupled by a thio-ether bond at the non-reducing terminal end and a reactive moiety at the reducing end, allowing for the creation of glycopeptides and glycosylated oligonucleotides that can be linked to peptides or nucleotides via click chemistry, mimicking native carbohydrate-decorated antigens to induce immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional glycoconjugate vaccines use Manα1→2Man moieties of high mannose glycans, then the immune response is directed against the glycan core, but the antibody response is degraded by mannosidase trimming and does not target the glycan extremities
Solution Approach 1:
The patent changes the chemical linkage parameter from conventional glycosidic bonds to thio-ether bonds. This chemical modification prevents mannosidase trimming while maintaining the immunogenicity of the Manα1→2Man motif, thereby stabilizing the antibody response against glycan extremities and resolving the enzymatic degradation problem
Solution Approach 2:
The patent creates a synthetic oligosaccharide structure that copies the natural Manα1→2Man glycan motif but incorporates thio-ether linkages instead of natural glycosidic bonds. This copied structure maintains the immunogenic epitope while conferring resistance to enzymatic hydrolysis, allowing the vaccine to stabilize antibody responses
2Stability of the object's composition
If thio-ether bonds are used to stabilize the oligosaccharide structure, then enzymatic hydrolysis is resisted, but the synthesis complexity increases
Solution Approach 1:
The patent segments the oligosaccharide synthesis into modular steps, building the thio-ether linked structure piece by piece. This segmentation approach manages the synthesis complexity by breaking down the complex thio-ether bond formation into manageable steps, while achieving the desired stability against enzymatic hydrolysis
Solution Approach 2:
The patent employs reactive moieties as intermediaries during the coupling process. These intermediaries facilitate the formation of thio-ether bonds between saccharide moieties, simplifying the synthesis process by providing a controlled mechanism for bond formation while maintaining the stability benefits of thio-ether linkages
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
These constructs stabilize the immune response against the glycan extremities, enhancing the effectiveness of glycoconjugate vaccines by resisting enzymatic hydrolysis and promoting the production of neutralizing antibodies.
Implementation Method 1
two saccharide moieties at a non-reducing terminal end of the oligosaccharide that are coupled together with a thio-ether bond
Implementation Method 2
one of the saccharide moieties at a reducing end of the oligosaccharide is coupled to a reactive moiety
Data Source
AI summary
Glycosylated peptides and oligonucleotides of the invention contain oligosaccharides that include three or more saccharide moieties, wherein two saccharide moieties at a non-reducing terminal end of the oligosaccharide are coupled together with a thio-ether bond, and one of the saccharide moieties at a reducing end of the oligosaccharide is coupled to a reactive moiety. Also disclosed are immunogenic conjugates that include a glycopeptide or oligonucleotide bound to an immunogenic carrier molecule, as well as pharmaceutical compositions containing the same.