5' Modified Nucleosides for Oligomeric Nuclease Stability
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Solution Overview
Problem
Current antisense compounds face challenges in achieving enhanced nuclease stability and specific targeting of disease-causing RNA sequences, limiting their therapeutic and diagnostic efficacy.
Innovation Solution
Development of 5′ modified nucleosides and analogs that are incorporated into oligomeric compounds, providing enhanced nuclease stability and the ability to hybridize with target RNA, thereby inhibiting its function, and used as primers and probes in diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used, then they can hybridize to target RNA and modulate gene expression, but they exhibit poor nuclease stability limiting their therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides at the 5′ terminal position of oligomeric compounds. Specifically, it introduces various chemical groups (alkyl, aryl, heteroaryl, cyclic alkyl, etc.) at the 5′ position to alter the physical and chemical properties of the compound, thereby enhancing resistance to nucleases while maintaining the ability to hybridize with target RNA and modulate gene expression.
Solution Approach 2:
The patent employs composite materials by combining modified nucleosides with standard nucleic acid sequences to create hybrid oligomeric compounds. These compounds integrate both natural and synthetic components, where the modified 5′ terminal nucleoside provides nuclease resistance while the remaining sequence maintains target specificity and hybridization capability, resulting in a composite structure with enhanced therapeutic properties.
2Reliability
If chemical modifications are introduced to enhance nuclease resistance, then stability improves, but compound complexity increases
Solution Approach 1:
The patent applies local quality by introducing chemical modifications only at the 5′ terminal position of the oligomeric compound rather than throughout the entire sequence. This localized modification approach provides sufficient nuclease resistance at the vulnerable terminal region while keeping the rest of the molecule simple and maintaining ease of synthesis and target hybridization.
3Manufacturing precision
If 5′ modified nucleosides are incorporated into oligomeric compounds, then nuclease stability and targeting specificity are enhanced, but synthesis complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the oligomeric compound into distinct segments: a modified 5′ terminal nucleoside segment and a standard nucleic acid sequence segment. This segmentation allows for modular synthesis where the modified terminal can be prepared separately and then coupled to the standard sequence, simplifying the overall manufacturing process while maintaining high targeting specificity.
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 5′ modified nucleosides and analogs enhance the stability and targeting specificity of oligomeric compounds, leading to effective inhibition of target RNA function and improved diagnostic capabilities.
Implementation Method 1
5′ modified nucleosides and analogs thereof are provided that are useful for incorporation at one of the terminal positions of an oligomeric compound
Implementation Method 2
the oligomeric compounds and compositions provided herein that incorporate one or more of these 5′ modified nucleosides or analog thereof 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, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. 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.