2′-Deoxy-2′-Fluoro-2′-C-Methyl Oligonucleotides for Gene Silencing
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Solution Overview
Problem
There is a need for effective nucleotides or modifications for dsRNA molecules that enhance the inhibition of target gene expression.
Innovation Solution
The development of oligonucleotides comprising 2′-geminal-substituted nucleosides, such as those described by formulas (I) and (II), which can be incorporated into dsRNA strands to improve gene silencing efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional dsRNA molecules are used for gene silencing, then gene expression inhibition can be achieved, but stability and activity are insufficient leading to reduced silencing efficiency
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides within dsRNA molecules. Specifically, it incorporates 2′-deoxy-2′-fluoro-2′-C-methyl nucleotides (where a fluorine atom and a methyl group are added at the 2′ position of the ribose sugar) to enhance both stability and gene silencing efficiency while maintaining the functional integrity of the dsRNA structure
Solution Approach 2:
The patent employs composite materials by creating hybrid nucleoside structures that combine elements from different chemical families. The 2′-deoxy-2′-fluoro-2′-C-methyl nucleotides integrate fluorinated sugar moieties with methyl group substitutions, forming composite nucleoside units that exhibit enhanced stability and activity compared to natural nucleotides
2Reliability
If conventional dsRNA molecules are used for gene silencing, then gene expression inhibition can be achieved, but off-target effects occur reducing overall efficacy
Solution Approach 1:
The patent applies local quality by introducing specific chemical modifications at particular positions within the dsRNA structure. The 2′-deoxy-2′-fluoro-2′-C-methyl nucleotides are incorporated at strategic locations to enhance on-target specificity and reduce off-target effects, while leaving other regions of the molecule unchanged to maintain overall functionality
Data Source
AI summary
The present disclosure relates generally to 2′-geminal substituted nucleosides and nucleotides, and oligonucleotides and dsRNA molecules comprising such 2′-geminal substituted nucleosides and nucleotides.