Modified Oligonucleotide Backbone for Stable Low-Toxicity RNA
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Solution Overview
Problem
Current RNA-based therapeutic strategies face issues with metabolic instability and toxicity due to non-specific binding of phosphorothioate (PS) and PS/PO-modified oligonucleotides, as well as challenges in synthesizing diverse chimeric backbones compatible with existing chemical modification methods.
Innovation Solution
Introduction of carbon chain insertions in the backbone structure to create block and cluster modifications at the termini of oligonucleotides, enhancing stability and compatibility with RNA-binding biological machineries while minimizing toxic interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If phosphorothioate (PS) modification is used to increase metabolic stability, then oligonucleotide stability is improved, but toxicity increases due to non-specific binding to proteins
Solution Approach 1:
The patent applies local quality by concentrating PS modifications at specific terminal regions (5' and/or 3' ends) rather than distributing them uniformly throughout the oligonucleotide. This creates localized blocks of modifications that provide metabolic stability at the ends while leaving internal regions unmodified to maintain specific binding capability and reduce non-specific protein interactions.
Solution Approach 2:
The oligonucleotide is segmented into modified terminal regions and unmodified internal regions. The terminal blocks contain the PS modifications for stability, while the internal segments remain unmodified to preserve specific target binding and reduce toxic non-specific binding to proteins.
2Stability of the object's composition
If PS/PO-modified RNAs are used to achieve metabolic stability, then stability is improved, but decomposition by endogenous nucleases occurs
Solution Approach 1:
The patent applies local quality by concentrating PS modifications at specific terminal regions (5' and/or 3' ends) rather than distributing them uniformly throughout the oligonucleotide. This creates localized blocks of modifications that provide metabolic stability at the ends while leaving internal regions unmodified to maintain specific binding capability and reduce non-specific protein interactions.
Solution Approach 2:
The patent uses composite backbone structures combining phosphorothioate (PS) and phosphoroamidate (PO) modifications in specific patterns. This composite approach creates a hybrid modification system that provides enhanced metabolic stability while maintaining resistance to nuclease decomposition through the synergistic effects of different backbone chemistries.
3Stability of the object's composition
If diverse chimeric backbones are designed to provide higher metabolic stabilization, then stability is improved, but synthesis difficulty increases due to incompatibility with conventional phosphoramidite methods
Solution Approach 1:
The patent achieves universality by developing a chimeric backbone system that can be synthesized using the conventional phosphoramidite method, which is already widely established and compatible with existing oligonucleotide synthesis infrastructure. This allows diverse backbone modifications to be manufactured using a single, versatile synthetic platform rather than requiring multiple specialized synthesis methods.
Solution Approach 2:
The patent applies parameter changes by modifying specific positions in the oligonucleotide backbone (terminal regions) while keeping the overall structure compatible with standard synthesis parameters. This allows the use of conventional phosphoramidite chemistry with adjusted modification patterns to achieve enhanced stability without requiring fundamentally different synthesis conditions.
Data Source
AI summary
This disclosure relates to novel modified oligonucleotides with increased stability. The universal modified nucleotide sequences to increase the stability of an oligonucleotide are also provided.