Halogenated Cyclohexenyl Nucleic Acids for Nuclease Resistance
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Solution Overview
Problem
There is a need for agents that specifically regulate gene expression via antisense mechanisms, particularly for modulating pathways like RNaseH, RNAi, and dsRNA enzymes, where existing cyclohexenyl nucleic acids have limitations in enhancing properties such as nuclease resistance and target specificity.
Innovation Solution
Development of novel cyclohexenyl nucleic acid analogs with a cyclohexene ring system substituted with halogen atoms at the 2′-position, which can be incorporated into oligomeric compounds to enhance properties like nuclease resistance and enable specific hybridization with target RNA, leading to the loss of normal RNA function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclohexenyl nucleic acids are used to replace furanose rings, then nuclease resistance is enhanced, but target specificity and hybridization efficiency may be compromised
Solution Approach 1:
The patent applies local quality by introducing halogen atoms at specific positions (2'-position) of the cyclohexenyl ring system. This localized modification enhances nuclease resistance at the sugar position while maintaining base pairing specificity through the heterocyclic base moieties, thus resolving the contradiction between stability and target recognition.
Solution Approach 2:
The patent modifies the chemical parameters of the cyclohexenyl nucleic acid by incorporating halogen substituents (fluoro, chloro, bromo, iodo) at the 2'-position. These parameter changes alter the electronic and steric properties of the sugar ring, enhancing nuclease resistance while preserving hybridization capability through optimized bond lengths and angles.
2Reliability
If halogen atoms are substituted at the 2′-position of the cyclohexene ring, then nuclease resistance is enhanced, but synthesis complexity increases
Solution Approach 1:
The patent employs preliminary action by incorporating halogenated cyclohexenyl nucleosides as building blocks in the oligonucleotide synthesis process. The halogenated monomers are prepared in advance and then incorporated during solid-phase synthesis, allowing the complex halogenated structures to be assembled systematically without requiring complex stepwise halogenation of the final product.
3Stability of the object's composition
If cyclohexenyl ring system is used instead of furanose ring, then chemical stability is improved, but biological activity and gene expression modulation may be reduced
Solution Approach 1:
The patent achieves universality by designing cyclohexenyl nucleic acids that can function through multiple mechanisms: RNase H-mediated degradation, RNA interference, and direct transcriptional inhibition. The halogenated cyclohexenyl scaffold provides chemical stability while the heterocyclic base moieties maintain compatibility with various biological targets, enabling multi-functional therapeutic applications.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The cyclohexenyl nucleic acid analogs effectively hybridize with target RNA, inhibiting its function and providing enhanced nuclease resistance, making them suitable for therapeutic and diagnostic applications in modulating gene expression.
Implementation Method 1
the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
The present disclosure describes cyclohexenyl nucleic acid analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, cyclohexenyl nucleic acid analogs are provided, having one or more chiral substituents, that are expected to be useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.