Modified Oligonucleotides with 2'-Sugar and Nucleobase Changes
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Solution Overview
Problem
Current oligonucleotides lack customized properties for enhanced binding to target strands, cell penetration, stability against nucleases, and improved pharmacokinetic properties, necessitating new modifications to increase melting temperatures and therapeutic efficacy.
Innovation Solution
Development of modified nucleosides and oligonucleotides with 2′-sugar modifications, high-affinity nucleobase modifications, and phosphate or phosphate mimic termini, including G-clamp and phenoxazine analogs, to enhance binding, stability, and cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemical modifications are introduced into oligonucleotides to increase binding affinity and stability, then therapeutic efficacy is improved, but molecular complexity and synthesis difficulty increase
Solution Approach 1:
The patent applies parameter changes by systematically modifying the sugar moiety of nucleosides (e.g., 2′-O-alkyl modifications, 2′-fluoro substitutions) to optimize the balance between binding affinity, nuclease resistance, and pharmacokinetic properties. Each modification represents a controlled change in molecular parameters that enhances therapeutic efficacy while managing complexity through structured chemical variation
Solution Approach 2:
The invention employs composite materials by combining modified nucleosides with specific nucleobases (including high-affinity modifications like G-clamp and phenoxazines) and various phosphate linkages (phosphorothioate, phosphodithioate, boranophosphate) to create oligonucleotides with tailored properties that achieve superior therapeutic performance through synergistic combinations of different molecular components
2Duration of action of stationary object
If chemical modifications are introduced to stabilize oligonucleotides against nucleases, then durability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent addresses manufacturing complexity by implementing systematic parameter changes in the sugar modification patterns (2′-O-alkyl, 2′-fluoro, 2′-methoxy) and phosphate linkage types, which allow for controlled enhancement of nuclease resistance while maintaining compatibility with existing solid-phase synthesis methodologies and enabling scalable production
Solution Approach 2:
The invention applies local quality by introducing modifications at specific positions within the oligonucleotide sequence (such as terminal modifications, periodic patterns, or cluster distributions) rather than uniform modification throughout, which optimizes nuclease protection while simplifying synthesis by limiting the number of modified building blocks required
3Force
If high-affinity nucleobase modifications are incorporated, then binding strength is improved, but synthesis difficulty increases
Solution Approach 1:
The patent implements local quality by incorporating high-affinity nucleobase modifications (G-clamp, phenoxazines, bi- and tricyclic bases) at specific strategic positions within the oligonucleotide rather than throughout the entire sequence, which maximizes binding strength to the target while reducing synthesis complexity by limiting the number of specialized building blocks that must be manufactured and handled
Data Source
AI summary
The present invention provides nucleosides of formula (1) and oligonucleotides comprising at least one nucleoside of formula (2):Another aspect of the invention relates to a method of inhibiting the expression of a gene in cell, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.