Variable Bridging Bicyclic Nucleosides for Antisense Stability
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Solution Overview
Problem
Current bicyclic nucleosides, such as LNA, face challenges in therapeutic applications due to hepatotoxicity and limited nuclease resistance, which hinders their effectiveness in antisense technology for gene expression modulation and diagnostic uses.
Innovation Solution
Development of novel bicyclic nucleosides with a variable alkyl, alkenyl, or heteroalkyl bridging group connecting the 3′ and 5′-positions of the ribose ring, enhancing properties like nuclease resistance and hybridization capabilities, and their incorporation into oligomeric compounds for targeted RNA modulation and diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If LNA (locked nucleic acid) is used to enhance hybridization stability and nuclease resistance, then binding affinity improves, but hepatotoxicity increases
Solution Approach 1:
The patent applies parameter changes by systematically varying the bridging group structure (different alkyl, alkenyl, or heteroalkyl groups with different lengths and compositions) to modify the conformational constraints of the ribose ring. This allows optimization of the balance between nuclease resistance and cellular toxicity by adjusting the degree of ring locking without completely rigidifying the structure, thereby reducing hepatotoxicity while maintaining therapeutic efficacy
Solution Approach 2:
The invention creates composite nucleoside structures by combining the heterocyclic base with modified ribose containing variable bridging groups. These composite bicyclic nucleosides are then incorporated into oligomeric compounds with specific patterns (e.g., gaps, clusters) to achieve both high nuclease resistance and reduced hepatotoxicity through controlled distribution of the modified units within the oligomer sequence
2Stability of the object's composition
If bicyclic nucleosides are incorporated into oligomeric compounds to enhance stability, then nuclease resistance improves, but the structural complexity increases
Solution Approach 1:
The patent segments the bicyclic nucleoside structure into modular components: a standardized heterocyclic base portion and a variable bridging group portion connecting the 3′ and 5′ positions of the ribose ring. This segmentation allows systematic variation of only the bridging group (with defined patterns such as -CH2-CH2-, -O-CH2-CH2-O-, -NH-CH2-CH2-NH-) to achieve desired stability while maintaining synthetic tractability and reducing overall molecular complexity
Solution Approach 2:
The variable bridging group design provides universal applicability across different nucleoside types (2′-deoxyribofuranosyl and ribofuranosyl) and different oligomer compositions. The same bridging group frameworks can be applied to various base sequences and oligomer lengths, enabling standardized synthesis protocols and reducing the complexity burden despite enhanced stability requirements
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 novel bicyclic nucleosides improve the stability and binding affinity of oligomeric compounds, enabling effective hybridization with target RNA and potential use as primers and probes, while minimizing toxicity and enhancing diagnostic capabilities.
Implementation Method 1
the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
The present invention provides novel 3′,5′-linked bicyclic nucleosides and oligomeric compounds prepared therefrom. The bicyclic nucleosides provided herein are useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as nuclease resistance.