5′ Modified Nucleosides for Nuclease-Stable Antisense Oligomers
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Solution Overview
Problem
Current antisense compounds face challenges in achieving enhanced nuclease stability and specific targeting of disease-causing gene sequences, limiting their therapeutic and diagnostic efficacy.
Innovation Solution
Development of 5′ modified nucleosides and oligomeric compounds with enhanced nuclease stability, designed to hybridize with target RNA, thereby inhibiting its normal function, and used as primers and probes in diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard nucleosides are used in antisense compounds, then the compounds can be synthesized and incorporated into oligomers, but the resulting oligomers exhibit poor nuclease stability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides at the 5' position with various groups including alkyl, aryl, heteroaryl, and cyclic groups. These structural parameter changes enhance nuclease stability while maintaining the ability to hybridize with target RNA sequences, directly resolving the contradiction between nuclease stability and chemical stability.
Solution Approach 2:
The patent employs composite materials by creating oligomeric compounds that incorporate modified nucleosides with specific 5' substitutions into the oligomer structure. This composite approach combines the stability benefits of modified nucleosides with the functional properties of oligomeric sequences, achieving both improved nuclease stability and maintained chemical stability.
2Reliability
If chemical modifications are introduced to enhance nuclease resistance, then oligomer stability improves, but the complexity of synthesis and incorporation increases
Solution Approach 1:
The patent applies local quality by introducing modifications specifically at the 5' position of nucleosides rather than throughout the entire molecule. This localized modification approach provides nuclease resistance at the vulnerable terminal positions while keeping the rest of the oligomer structure simple and easy to synthesize, thereby reducing overall synthesis complexity.
Solution Approach 2:
The patent uses segmentation by providing modified nucleosides as separate, pre-synthesized building blocks that can be incorporated into oligomers during standard oligonucleotide synthesis. This segmentation allows the complex modified nucleosides to be prepared independently and then assembled into the final oligomeric structure, simplifying the overall synthesis process.
3Reliability
If 5' modified nucleosides are incorporated into oligomers, then nuclease stability is enhanced, but the cost and difficulty of manufacturing increase
Solution Approach 1:
The patent applies self-service by providing comprehensive synthetic routes and methods for preparing the modified nucleosides and incorporating them into oligomers. The patent includes detailed procedures for synthesizing various 5' modified nucleosides and their incorporation into oligomeric compounds, enabling manufacturers to produce these stable compounds without requiring external specialized services or processes.
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 oligomeric compounds demonstrate improved nuclease stability and specific RNA targeting, enhancing their therapeutic potential and diagnostic utility by effectively inhibiting gene expression and facilitating disease treatment.
Implementation Method 1
the oligomeric compounds and compositions provided herein that incorporate one or more of these modified nucleosides 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 5′ modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5′-substituent and an optional 2′ 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.