Modified Oligonucleotides with Formula I Linking Groups
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Solution Overview
Problem
Current antisense technology faces challenges in achieving efficient and specific modulation of gene expression, particularly in therapeutic applications, due to limitations in nuclease resistance, pharmacokinetics, and target specificity.
Innovation Solution
The development of oligomeric compounds comprising modified oligonucleotides with specific chemical modifications, such as those described in the Sequence Listing, which include internucleoside linking groups of Formula I, enhance nuclease resistance and improve pharmacokinetic properties while maintaining sequence specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used, then sequence specificity is achieved, but nuclease resistance and pharmacokinetic properties are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of antisense compounds through specific internucleoside linking groups (Formula I) with varying R substituents (aryl, heterocycle, alkyl, etc.) and X configurations (O or S). These structural parameter modifications enhance nuclease resistance and pharmacokinetic properties while maintaining sequence specificity, directly resolving the contradiction between reliability and device complexity.
Solution Approach 2:
The patent employs composite materials by combining modified oligonucleotides with specific chemical modifications (Formula I linking groups) to create enhanced antisense compounds. This composite approach integrates multiple functional elements (nuclease resistance, improved pharmacokinetics, maintained specificity) into a single modified oligonucleotide structure, addressing the technical contradiction effectively.
2Stability of the object's composition
If chemical modifications are introduced to enhance stability and pharmacokinetics, then nuclease resistance improves, but manufacturing complexity increases
Solution Approach 1:
The patent uses parameter changes by systematizing chemical modifications through Formula I with defined R and X parameters. This structured approach to modification allows for predictable stability enhancements while providing a framework for standardized synthesis procedures, thereby improving oligonucleotide stability without proportionally increasing manufacturing complexity.
3Manufacturing precision
If existing antisense compounds are used, then gene expression modulation is achieved, but delivery efficiency and specificity are limited
Solution Approach 1:
The patent applies parameter changes by modifying the chemical and structural parameters of antisense compounds through Formula I linking groups. These modifications enhance both target specificity (through maintained sequence complementarity) and delivery efficiency (through improved pharmacokinetics and stability), simultaneously addressing the contradiction between manufacturing precision and productivity.
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 modified oligonucleotides demonstrate enhanced stability, improved delivery, and increased specificity in modulating gene expression, thereby overcoming the limitations of existing antisense technologies.
Implementation Method 1
an antisense compound hybridizes to a target nucleic acid and modulates the amount, activity, and/or function of the target nucleic acid
Implementation Method 2
target RNA degradation or occupancy-based inhibition. An example of modulation of RNA target function by degradation is RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound
Data Source
AI summary
The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one chemical modification.