3' End Caps for RNAi Agents Enhancing Serum Stability
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Solution Overview
Problem
RNAi agents have a short biological half-life in blood serum due to degradation, limiting their therapeutic use, as naked RNAi agents are often degraded within minutes, and existing modifications do not effectively enhance both RNA interference activity and duration of activity.
Innovation Solution
The development of novel RNAi agents with a 3′ end cap, specifically compounds of formula Ia and Ib, which include a spacer and a modified internucleoside linker, attached to a solid support, to increase stability and duration of action by reducing nuclease degradation and improving loading into the RISC complex.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If naked RNAi agents are used, then RNA interference activity is achieved, but biological half-life in blood serum is short due to degradation
Solution Approach 1:
The patent applies preliminary action by pre-modifying the RNAi agent structure before administration. Specifically, 3′ end caps are added to the RNAi agent strands, and phosphorothioate modifications are introduced at strategic positions. These preliminary structural modifications protect the RNAi agent from nuclease degradation before it enters the bloodstream, thereby extending its biological half-life while maintaining its RNA interference activity.
Solution Approach 2:
The patent employs composite materials by combining different chemical modifications within the RNAi agent structure. The RNAi agent comprises a mixture of strands with various 3′ end cap structures (different chemical groups at the 3′ end) and phosphorothioate modifications at different positions. This composite approach creates a population of RNAi agents with enhanced stability and extended half-life in blood serum while preserving target-specific gene silencing activity.
2Duration of action of stationary object
If RNAi agents are modified to increase stability, then duration of action is prolonged, but RNA interference activity may be reduced
Solution Approach 1:
The patent applies local quality by making modifications only at specific locations on the RNAi agent molecules rather than throughout the entire structure. Phosphorothioate modifications are placed at particular positions (e.g., positions 1-2 from the 3′ end), and 3′ end caps are added only to the terminal nucleotides. These localized modifications provide stability enhancement without interfering with the critical base-pairing regions that mediate RNA interference activity, thus maintaining productivity while extending duration of action.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying the chemical parameters of the RNAi agent structure. Different 3′ end cap chemistries are tested (e.g., different chemical groups), and the number and position of phosphorothioate modifications are adjusted. Through these parameter optimizations, the patent identifies configurations that maximize both stability (duration of action) and RNA interference activity (productivity), resolving the contradiction between these two parameters.
Data Source
AI summary
The disclosure relates to novel compounds and compositions comprising a RNAi agent comprising a novel compound as a 3′ end cap. The disclosure also relates to processes for making such compositions, and methods and uses of such compositions, e.g., to mediate RNA interference.