Chirally Controlled CpG Oligonucleotides for TLR9 Activity
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Solution Overview
Problem
Existing oligonucleotides, including those with CpG region motifs, lack effective control over structural elements such as base sequence, chemical modifications, and stereochemistry, leading to unpredictable immunomodulatory activities and stability, particularly in TLR9 agonist and antagonist functions.
Innovation Solution
Development of chirally controlled oligonucleotide compositions with predetermined stereochemistry of internucleotidic linkages, including phosphorothioate configurations, to modulate TLR9-related activities and improve stability, utilizing lipid conjugation and specific structural patterns.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If oligonucleotides are synthesized with conventional methods, then production is simpler and faster, but structural control (stereochemistry, chemical modifications) is poor leading to unpredictable activity
Solution Approach 1:
The oligonucleotide synthesis process is divided into discrete steps where specific chiral centers are formed at defined positions. Each internucleotidic linkage is created with controlled stereochemistry through sequential addition of nucleotides with predetermined configurations, allowing precise structural control while maintaining manageable synthesis complexity.
Solution Approach 2:
Chiral auxiliaries and stereospecific reagents are introduced during the synthesis process to pre-establish the desired stereochemistry at each chiral center. This preliminary action ensures that the final oligonucleotide possesses the intended three-dimensional structure and chiral configuration, enabling predictable immunomodulatory activity.
2Reliability
If oligonucleotides have controlled stereochemistry and chemical modifications, then immunomodulatory activity and stability are improved, but synthesis complexity and cost increase
Solution Approach 1:
The synthesis methodology employs controlled changes in reaction parameters such as temperature, pH, and reagent concentration to achieve specific stereochemical outcomes. By optimizing these parameters at each step, the process achieves reliable activity predictability while maintaining reasonable synthesis ease through established chemical principles.
Solution Approach 2:
Chiral auxiliaries and stereospecific coupling reagents serve as intermediaries that facilitate the formation of bonds with predetermined stereochemistry. These intermediaries enable precise control over the three-dimensional arrangement of nucleotides without requiring complex multi-step procedures, thus improving reliability while maintaining manufacturing feasibility.
3Productivity
If lipid moieties are conjugated to oligonucleotides, then delivery and pharmacokinetics are improved, but structural complexity increases
Solution Approach 1:
Lipid moieties are covalently conjugated to the oligonucleotide backbone or terminal groups, merging the delivery capabilities of lipids with the nucleic acid sequence information. This combination enables improved cellular uptake and pharmacokinetic properties while the conjugation is achieved through established chemical methods that do not excessively increase structural complexity.
Solution Approach 2:
The oligonucleotide-lipid conjugate represents a composite material combining nucleic acid and lipid components. This composite structure leverages the complementary properties of both molecules: the sequence-specific binding of the oligonucleotide and the membrane-interacting, delivery-enhancing properties of the lipid, achieving improved productivity without proportionally increasing complexity.
Data Source
AI summary
The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.