Acyclic Abasic Oligonucleotides for Nuclease Stability
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Solution Overview
Problem
Current oligonucleotides lack effective modifications for enhanced stability, cell penetration, and targeted gene inhibition, limiting their therapeutic and diagnostic applications.
Innovation Solution
Development of acyclic and abasic nucleosides and oligonucleotides with specific monomers that can be incorporated into oligonucleotides, providing conformational locking and reactive phosphorus groups for forming internucleoside linkages, which can be used to inhibit gene expression by contacting cells with modified oligonucleotides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oligonucleotides are used, then they can hybridize to target nucleic acid, but they lack sufficient stability and cell penetration for therapeutic applications
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides through acyclic modifications and abasic group introductions. These structural parameter changes enhance oligonucleotide stability against nucleases while maintaining hybridization capability, enabling therapeutic applications that were previously limited by degradation and poor cell penetration
Solution Approach 2:
The patent employs composite materials by combining acyclic nucleoside components with abasic group modifications to create hybrid oligonucleotide structures. This composite approach integrates the stability benefits of acyclic modifications with the enhanced cell penetration and nuclease resistance provided by abasic groups, achieving multiple therapeutic requirements simultaneously
2Reliability
If chemical modifications are introduced to increase binding and stability, then therapeutic potential improves, but molecular complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the nucleoside structure into distinct functional components: the acyclic sugar moiety provides stability, while separate abasic group modifications enhance cell penetration. This segmentation allows each component to contribute specific properties without requiring complex integrated structures, simplifying the overall molecular design while achieving multiple therapeutic benefits
Data Source
AI summary
This invention relates to an oligonucleotide comprising one or more abasic nucleoside monomers of formula V:These monomers are useful for modifying of oligonucleotides at one or more positions. This invention also relates to a method of inhibiting the expression of a target gene in a cell. The method comprises contacting the cell with an oligonucleotide having one or more of the above formula (V).