2'-Amino Bicyclic Nucleosides for Antisense RNA Hybridization
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Solution Overview
Problem
Current antisense compounds for modulating gene expression face challenges in enhancing binding affinity and stability, particularly in hybridizing with target RNA, which affects their therapeutic and diagnostic efficacy.
Innovation Solution
Development of novel 2'-amino and 2'-thio bicyclic nucleosides with additional substituent groups, incorporated into oligomeric compounds, to enhance properties such as binding affinity and nuclease resistance, allowing them to hybridize with target RNA and modulate gene expression effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used to modulate gene expression, then they can hybridize with target RNA, but their binding affinity and stability are insufficient
Solution Approach 1:
The patent employs composite nucleoside structures combining bicyclic frameworks with 2'-amino or 2'-thio modifications. This composite approach integrates multiple functional elements (bicyclic rigidity for binding affinity, 2'-amino/thio groups for nuclease resistance) into a single nucleoside unit, thereby simultaneously improving both binding affinity and stability against nucleases in the antisense compound
Solution Approach 2:
The invention introduces specific local modifications at the 2' position of the ribose sugar (amino or thio groups) and incorporates bicyclic base structures. These localized quality enhancements at critical positions improve the overall performance: the 2'-amino/thio groups provide steric protection against nucleases while the bicyclic structure enhances stacking interactions and binding affinity with target RNA
2Reliability
If chemical modifications are introduced to enhance potency, then binding affinity increases, but compound complexity increases
Solution Approach 1:
The bicyclic nucleoside structure can be viewed as segmented into distinct functional domains: the bicyclic aromatic system providing binding affinity through stacking interactions, and the 2'-amino or 2'-thio substituted sugar moiety providing nuclease resistance. This segmentation allows each domain to be optimized independently while maintaining overall structural coherence and manageable complexity
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 demonstrate improved activity with low toxicity, effectively hybridizing with target RNA to inhibit its normal function, and are useful as primers and probes in diagnostic applications, offering enhanced stability and specificity.
Implementation Method 1
the oligomeric compounds provided herein have been shown to hybridize to a portion of a target RNA resulting in moderation of normal function of the target RNA
Data Source
AI summary
Provided herein are 2'-amino and 2'-thio bicyclic nucleosides and oligomenc compounds prepared therefrom. The novel bicyclic nucleosides provided herein are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as nuclease resistance.