Modified Oligonucleotide Monomers for Stronger dsRNA Gene Silencing

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for effective nucleotide or chemical motifs for dsRNA molecules that enhance the inhibition of target gene expression.

Innovation Solution

The development of compounds of Formula (I) with specific functional groups and linkers for modified oligonucleotides, including RMA moieties, which can be used to synthesize single-stranded oligonucleotides and dsRNAs, enhancing their gene-specific silencing capabilities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional nucleotide motifs are used for dsRNA molecules, then basic gene silencing function is achieved, but silencing efficacy is insufficient

Engineering Contradiction:

Improvegene silencing efficacyVSAvoidinhibition capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure of nucleotide motifs by changing parameters such as introducing RMA moieties with specific linkers (e.g., -O(CH2)m1-XM'-RM' or -O(CH2)n1-C(YM)N(RN')(RN'')) and varying m1, n1, and other structural parameters to optimize silencing efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite nucleotide structures combining multiple functional groups and linkers (e.g., phosphorothioate linkages, RMA moieties, and various linker configurations) to achieve enhanced silencing activity that cannot be obtained with single-component nucleotides

Inventive Principle:

Principle #40Composite materials

2Reliability

If modified oligonucleotides with RMA moieties are synthesized, then gene-specific silencing capability is enhanced, but synthesis complexity increases

Engineering Contradiction:

Improvegene-specific silencing capabilityVSAvoidsynthesis process complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent divides the oligonucleotide synthesis process into modular steps, with RMA moieties and linkers being introduced at specific positions during the synthesis process, allowing for systematic construction of complex structures

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention uses protective groups and intermediates (such as those mentioned in the synthesis method with formulae I and II) to facilitate the stepwise construction of RMA-containing oligonucleotides, enabling complex structures to be built from simpler components

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250382324A1Monomers and methods for synthesis of modified oligonucleotides

Publication Date: 2025.12.18 ALNYLAM PHARMACEUTICALS INC

AI summary

The present disclosure relates to monomers and methods for synthesizing modified oligonucleotides.