Substituted α-L-Bicyclic Nucleosides Enhance RNA Binding Affinity
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Solution Overview
Problem
There is a long-felt need for agents that specifically regulate gene expression via antisense mechanisms, as existing technologies have limitations in effectively modulating gene expression pathways using RNaseH, RNAi, and dsRNA enzymes.
Innovation Solution
Substituted α-L-bicyclic nucleosides are developed, which are incorporated into oligomeric compounds to enhance their properties, such as affinity and nuclease resistance, allowing for specific regulation of gene expression by hybridizing with target RNA and inhibiting its function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemically modified nucleosides are used to enhance affinity and nuclease resistance, then the effectiveness of antisense sequences is improved, but the complexity of the chemical structure increases
Solution Approach 1:
The patent applies parameter changes by modifying the furanose ring structure through substitution with bicyclic nucleosides, altering the chemical parameters to achieve enhanced affinity and nuclease resistance while maintaining the antisense mechanism's effectiveness
Solution Approach 2:
The invention uses composite materials by incorporating substituted α-L-bicyclic nucleosides into the oligomeric antisense sequences, combining the benefits of bicyclic structure stability with the antisense mechanism to create a more effective and stable therapeutic agent
2Strength
If substituted α-L-bicyclic nucleosides are incorporated into oligomeric compounds to enhance affinity, then the binding strength to target RNA is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent applies local quality by introducing substituted α-L-bicyclic nucleosides at specific positions within the oligomeric sequence, enhancing binding affinity at critical interaction points while maintaining overall sequence functionality and managing manufacturing complexity through targeted modification
3Stability of the object's composition
If chemically modified nucleosides are used to improve nuclease resistance, then the stability of the oligomeric compound is enhanced, but the cost of production increases
Solution Approach 1:
The patent applies parameter changes by modifying the sugar backbone with substituted α-L-bicyclic structures, fundamentally altering the chemical parameters to achieve superior nuclease resistance and stability, which justifies the increased production cost through enhanced therapeutic effectiveness
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 substituted α-L-bicyclic nucleosides improve the activity of oligomeric compounds, enabling effective modulation of gene expression and potential therapeutic applications by enhancing their binding affinity and stability.
Implementation Method 1
the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
The present disclosure describes substituted α-L-bicyclic nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, substituted α-L-bicyclic nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.