Oligonucleotide Conjugation via Segmented Solid-Phase Synthesis
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Solution Overview
Problem
Current methods for liver-targeted delivery of oligonucleotides, such as those used by Alnylam and ISIS Pharmaceuticals, face limitations in synthesis efficiency, steric hindrance, and restricted modification sites, which affect the binding affinity and versatility of oligonucleic acid drugs.
Innovation Solution
A compound comprising an oligonucleotide conjugate with a single ASGPR ligand linked multiple times through solid-phase chemical synthesis, allowing for independent control of ligand spatial distance and position, expanding the scope of oligonucleic acid modifications and increasing synthesis efficiency and scalability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple ASGPR ligands are linked to oligonucleotide simultaneously using conventional methods, then binding affinity is improved, but synthesis efficiency decreases and steric hindrance increases
Solution Approach 1:
The patent divides the ligand conjugation process into separate steps: first synthesizing the oligonucleotide with a terminal group, then independently conjugating ASGPR ligands to the terminal group in separate reaction steps. This segmentation allows controlled addition of multiple ligands without the steric hindrance and efficiency losses of simultaneous conjugation methods.
Solution Approach 2:
The patent performs preliminary synthesis of the oligonucleotide with a reactive terminal group (such as phosphoramidite or phosphotriester) before conjugating the ASGPR ligands. This preliminary preparation creates a ready-to-conjugate platform that enables efficient, stepwise ligand addition without the need for complex simultaneous conjugation chemistry.
2Reliability
If ASGPR ligands are conjugated to oligonucleotide terminals, then liver targeting is achieved, but modification sites are restricted
Solution Approach 1:
The patent creates a universal conjugation platform where the terminal group (phosphoramidite, phosphotriester, or other reactive groups) can be conjugated to various types of ASGPR ligands including GalNAc, Gal, and their derivatives. This single terminal modification system enables multiple ligand types to be attached, expanding versatility while maintaining liver targeting capability.
Solution Approach 2:
The patent explores different chemical parameters of the terminal group (such as changing from phosphoramidite to phosphotriester, or adjusting the chemical structure of the conjugating group) to enable different ligand types and conjugation chemistries. This parameter variation allows the same basic terminal modification approach to accommodate diverse ligand structures and conjugation requirements.
3Reliability
If conventional ligand conjugation methods are used, then liver targeting is achieved, but steric hindrance affects binding affinity
Solution Approach 1:
The patent extracts the ligand conjugation step from the oligonucleotide synthesis process, separating it into a distinct post-synthesis modification step. This extraction allows the use of smaller, less sterically hindered terminal groups that can be easily replaced or modified without the steric constraints of integrated synthesis methods, thereby improving binding affinity while maintaining targeting.
Data Source
AI summary
The present disclosure falls within the field of biomedical technology, and in particular relates to modified oligonucleotides and a compound that can be used for synthesizing same and a method for modifying oligonucleotides. The present disclosure also relates to the use of the modified oligonucleotides for preventing and/or treating diseases associated with the liver in a subject.