N-Substituted Aminomethylene Bicyclic Nucleic Acids for Antisense Therapy
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Solution Overview
Problem
There is a need for agents that specifically regulate gene expression via antisense mechanisms without causing significant hepatotoxicity, as recent antisense oligonucleotides containing locked nucleic acids have shown hepatotoxicity in animals.
Innovation Solution
Development of N-substituted aminomethylene bridged bicyclic nucleic acid analogs and antisense oligomeric compounds that hybridize to target RNA, modulating gene expression pathways through mechanisms like RNaseH, RNAi, and dsRNA enzymes, without exhibiting hepatotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If locked nucleic acids (LNA) are used in antisense oligonucleotides to enhance binding affinity and nuclease resistance, then the efficacy of gene expression regulation is improved, but hepatotoxicity occurs in animals
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of bicyclic nucleosides through N-substitution with various groups (alkyl, alkenyl, alkynyl, and their substituted forms). These structural parameter changes maintain the beneficial binding affinity and nuclease resistance while eliminating hepatotoxicity. The specific substitutions at positions q1-q4 and the bridge modification (N-substituted aminomethylene) represent systematic parameter changes to the molecular structure.
Solution Approach 2:
The patent employs composite materials by creating chimeric oligomeric compounds that combine different types of nucleosides and nucleotides within a single molecule. The compounds integrate modified bicyclic nucleosides with natural or other modified nucleotides, allowing optimization of different regions for binding affinity, stability, and reduced toxicity. This composite approach enables simultaneous achievement of high efficacy and reduced hepatotoxicity.
2Duration of action of stationary object
If bicyclic nucleosides with increased nuclease resistance are developed to improve stability, then the duration of action is extended, but the complexity of chemical synthesis increases
Solution Approach 1:
The patent applies segmentation by dividing the oligomeric compound into distinct regions with different functions: modified bicyclic nucleoside regions for enhanced stability and nuclease resistance, and other regions for binding affinity and cellular uptake. This segmentation allows independent optimization of each region's properties and facilitates modular synthesis approaches, reducing overall complexity.
Solution Approach 2:
The patent implements universality by designing bicyclic nucleoside structures that serve multiple functions simultaneously: they provide nuclease resistance, maintain binding affinity through complementary base pairing, and enable controlled pharmacokinetic properties. The N-substituted aminomethylene bridge structure universally applies across different nucleoside types (A, G, C, U bases) to achieve these combined effects.
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 oligomeric compounds show good activity both in vitro and in vivo with 80% relative activity compared to similar compounds, and a 37-55 fold increase in nuclease resistance, while avoiding significant hepatotoxicity.
Implementation Method 1
the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Implementation Method 2
Chemically modified nucleosides are routinely incorporated into antisense oligomeric compounds to enhance one or more properties such as nuclease resistance
Data Source
AI summary
Provided herein are bicyeMc nucleosides comprising a substituted amino group in the bridge, oligomeric compounds having at least one of these bicyclic nucleosides and methods of using the oligomeric compounds. The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for enhancing properties of oligomeric compounds including nuclease resistance, in certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.