Bridged Nucleoside Structure for Nuclease-Resistant mRNA Binding
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Solution Overview
Problem
Existing bridged nucleosides and nucleotides are susceptible to decomposition by nuclease in vivo and lack high binding affinity and specificity for target mRNA, limiting their effectiveness in regulating gene expression.
Innovation Solution
Development of novel bridged nucleosides and nucleotides represented by specific chemical formulas with various substituents, including purin-9-yl and 2-oxo-1,2-dihydropyrimidin-1-yl groups, which enhance resistance to nuclease degradation and improve binding affinity for single-stranded RNA and DNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing bridged nucleosides and nucleotides are used, then they can bind to target RNA/DNA, but they are susceptible to decomposition by nuclease in vivo
Solution Approach 1:
The patent modifies the chemical structure of nucleosides and nucleotides by introducing bridged morpholino rings at the 2'- and 4'-positions of the ribose moiety. This structural parameter change creates a conformational lock that prevents nuclease recognition and degradation, while maintaining the ability to form complementary base pairs with target RNA and DNA sequences.
Solution Approach 2:
The invention creates composite nucleoside structures combining the natural nucleobase (purine or pyrimidine) with a modified sugar moiety featuring the bridged morpholino ring system. This composite structure integrates the binding specificity of natural nucleotides with the enhanced nuclease resistance provided by the artificial bridged ring structure.
2Reliability
If existing bridged nucleosides and nucleotides are used, then they can regulate gene expression, but they lack high binding affinity and specificity for target mRNA
Solution Approach 1:
The patent introduces specific substituents at defined positions on the bridged morpholino ring structure (such as alkyl groups, alkoxy groups, and other functional groups at the 6-position). These local modifications enhance the binding affinity and specificity for target mRNA sequences by optimizing steric fit and intermolecular interactions at the binding interface.
Solution Approach 2:
The invention systematically varies chemical parameters including the type of substituents, their positions, and their stereochemistry to optimize binding properties. The bridged structure itself represents a parameter change from conventional nucleosides, creating a rigid conformation that pre-organizes the molecule for high-affinity binding to target sequences.
Data Source
AI summary
[Problem]Provision of bridged nucleosides and nucleotides that are less susceptible to decomposition by nuclease in vivo, have high binding affinity and specificity for the target mRNA, and can efficiently regulate the expression of specific genes.[Solving Means]A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:in the formula (I), Base shows a purin-9-yl group or a 2-oxo-1,2-dihydropyrimidin-1-yl group optionally having one or more substituents, R1 and R2 are each independently a hydrogen atom or the like, and R3 and R4 are each independently a hydrogen atom or the like.