Bis-modified Bicyclic Nucleosides Nuclease Resistance
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Solution Overview
Problem
There is a need for agents that can specifically regulate gene expression via antisense mechanisms, particularly those utilizing RNaseH, RNAi, and dsRNA enzymes, as existing bicyclic nucleosides with single or no substituents on the bridge do not fully address the requirement for enhanced nuclease resistance and target RNA modulation.
Innovation Solution
Development of novel bis-modified bicyclic nucleosides with non-H substituent groups on the bridge and 5'-methylene group, which are incorporated into oligomeric compounds to enhance properties such as nuclease resistance and enable hybridization with target RNA, leading to loss of normal function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bicyclic nucleosides with single or no substituents on the bridge are used, then the structure is simpler and easier to manufacture, but nuclease resistance and target RNA modulation are insufficient
Solution Approach 1:
The patent applies composite material principles by combining multiple substituent groups (Q and Z) on the bicyclic nucleoside structure. The bridge position receives substituent Q while the 5'-methylene group receives substituent Z, creating a composite modified nucleoside that achieves enhanced nuclease resistance through the synergistic effect of multiple chemical modifications rather than relying on a single substituent
Solution Approach 2:
The patent implements local quality modification by placing specific substituent groups at distinct positions on the nucleoside structure. Substituent Q is positioned on the bridge (2'-O-C(Q1)(Q2)-4') while substituent Z is positioned on the 5'-methylene group, allowing different regions of the molecule to contribute differently to nuclease resistance and target RNA modulation
2Ease of manufacture
If bicyclic nucleosides with single substituent on the bridge are used, then the manufacturing process is less complex, but the ability to hybridize with target RNA and modulate gene expression is limited
Solution Approach 1:
The patent applies segmentation by dividing the modification strategy into two separate substituent positions: substituent Q on the bridge and substituent Z on the 5'-methylene group. This segmented approach allows each substituent to be optimized for specific functions (hybridization affinity, nuclease resistance, or gene expression modulation) while maintaining modular synthesis capabilities
Solution Approach 2:
The patent implements parameter changes by systematically varying the chemical nature of substituents Q and Z at different positions on the bicyclic nucleoside. This allows optimization of multiple parameters simultaneously including hybridization affinity, nuclease resistance, and gene expression modulation capability through chemical structure-variable relationships
Data Source
AI summary
The present disclosure describes bis-modified bicyclic nucleosides and oligomeric compounds that can be prepared comprising at least one of these bis-modified bicyclic nucleosides. More particularly, the bis-modified bicyclic nucleosides have at least one substituent group at the 5'- methylene and on the bridge methylene and can be chiral. These bis-modified bicyclic nucleosides are expected to be useful for enhancing one or more property of oligomeric compounds including for example enhancing nuclease resistance.