5' and 2' Bis-Substituted Nucleosides for Nuclease Resistance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a long-felt need for agents that specifically regulate gene expression via antisense mechanisms, particularly for modulating pathways involving RNaseH, RNAi, and other antisense mechanisms based on target degradation or occupancy, which existing technologies have not adequately addressed.
Innovation Solution
The development of oligomeric compounds comprising monomers of Formula II, which are designed to hybridize with target RNA, thereby inhibiting its normal function, and are also useful as primers and probes in diagnostic applications, incorporating modified nucleosides with specific internucleoside linkages and heterocyclic bases to enhance properties such as nuclease resistance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If chemically modified nucleosides are used to enhance nuclease resistance and stability, then the duration of action and reliability improve, but the device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies parameter changes by systematically varying the chemical modifications at the 5' and 2' positions of the ribose sugar. Different substituent groups (R1, R2, R3, R4) are explored including alkyl, alkoxy, halogen, and other functional groups. This allows optimization of nuclease resistance and stability while maintaining manageable synthesis through structured chemical variation rather than complete structural redesign
Solution Approach 2:
The invention uses composite materials by combining modified nucleoside units with specific internucleoside linkages (phosphodiester, phosphorothioate, phosphoramidate) to create oligomeric compounds with enhanced properties. The composite structure integrates different chemical components (modified sugars, heterocyclic bases, varied linkages) to achieve superior nuclease resistance and stability while preserving hybridization capability
2Reliability
If chemically modified nucleosides with multiple substituents are incorporated into oligomeric compounds, then the reliability and affinity for target RNA improve, but the ease of manufacture decreases
Solution Approach 1:
The patent applies segmentation by dividing the oligomeric compound into repeating monomeric units, each containing a modified nucleoside with substituents at the 5' and 2' positions. This modular approach allows systematic synthesis where each unit can be prepared and then assembled into the full oligomer, making the manufacturing process more manageable despite the complexity of individual modified units
Solution Approach 2:
The invention employs universality by designing modified nucleoside structures that can serve multiple functions: they provide nuclease resistance, maintain or enhance target RNA hybridization affinity, and allow for systematic variation to optimize different therapeutic targets. The general Formula I structure can be applied across multiple oligomeric compounds for different disease targets
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
These oligomeric compounds effectively hybridize with target RNA to inhibit its function, offering potential therapeutic and diagnostic applications by modulating gene expression and providing enhanced stability and affinity.
Implementation Method 1
the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5'-substituent and a 2'-O-substituent, oligomeric compounds comprising at least one of these modified nucleosides and methods of using the oligomeric compounds. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.