Chiral CpG Oligonucleotide Stability and Toxicity Trade-off
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Solution Overview
Problem
CpG oligonucleotides with phosphorothioate backbone modifications induce inflammation and toxicity, and their stability is compromised when the modifications are removed, leading to reduced efficacy in immune cell activation.
Innovation Solution
Development of CpG oligonucleotides with a stable stereoisomer configuration, where only specific phosphate backbone modifications are introduced, enhancing in-vivo stability and biocompatibility without universal phosphorothioate modifications, and including sequences that promote interferon-α production and immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If phosphorothioate backbone modifications are introduced to enhance in-vivo stability, then stability is improved, but inflammation and toxicity increase
Solution Approach 1:
The patent applies local quality by introducing phosphorothioate modifications only at specific positions (5' and 3' ends) rather than throughout the entire backbone. This localized modification strategy provides stability where needed while minimizing the toxic effects associated with extensive phosphorothioate modification, thus resolving the contradiction between stability and toxicity.
Solution Approach 2:
The patent segments the phosphorothioate modifications into discrete positions along the oligonucleotide backbone, specifically at terminal regions. This segmentation allows the molecule to achieve sufficient stability for in-vivo application while reducing the overall burden of modifications that would otherwise cause inflammation and toxicity.
2Object-generated harmful factors
If phosphorothioate backbone modifications are removed to reduce toxicity, then biocompatibility is improved, but stability decreases
Solution Approach 1:
The patent implements local quality by concentrating phosphorothioate modifications at the 5' and 3' terminal positions rather than distributing them throughout the backbone. This localized approach maintains sufficient stability for in-vivo application while significantly reducing the toxic effects associated with extensive modification, thus resolving the contradiction between stability and biocompatibility.
3Stability of the object's composition
If all sequences are phosphorothioated to enhance stability, then in-vivo stability is improved, but cytotoxicity increases
Solution Approach 1:
The patent applies local quality by limiting phosphorothioate modifications to specific terminal positions (5' and 3' ends) rather than modifying all sequences throughout the backbone. This selective modification provides sufficient stability for in-vivo application while minimizing cytotoxic effects, thus resolving the contradiction between stability and cytotoxicity.
Solution Approach 2:
The patent segments the phosphorothioate modifications into discrete terminal positions, creating a pattern where only specific regions of the oligonucleotide are modified. This segmentation strategy achieves the necessary stability while reducing the overall cytotoxic burden compared to full backbone modification.
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 CpG oligonucleotides demonstrate improved stability, reduced cytotoxicity, and enhanced immune adjustment powers, making them effective for treating diseases by activating dendritic cells and inducing immunomodulatory factors.
Implementation Method 1
the S-form stereoisomer of CpG oligonucleotide trimer promotes MAPK signal... Following Non Patent Literature 1 discloses that the S-form stereoisomer of CpG oligonucleotide trimer promotes MAPK signal
Data Source
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AI summary
Problem The purpose of the present invention is to provide: a stereo isomer of a novel CpG oligonucleotide, which has excellent stability; and a CpG oligonucleotide which has a capability of producing interferon-α (IFNα). Solution The present invention relates to an oligonucleotide which contains two to four sequences each represented by the formula 5'-X1X2CpGX3X4-3' (formula (I)) and has a length of 14 to 32 nucleotides. In formula (I), CpG represents a non-methylated CpG residue having a phosphate skeleton modification, X1X2 represents any one of AA, AT, GA and GT, and X3X4 represents any one of TT, AT, AC and CG. The oligonucleotide has at least one phosphate skeleton modification at an S-form stereoisomer located at a site other than the CpG.