Liquid-Phase Oligonucleotide Synthesis With Soluble Alkyl Supports
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Solution Overview
Problem
Conventional solid phase oligonucleotide synthesis (SPOS) faces challenges such as low overall yield, high reagent costs, and difficulty in purifying mismatched oligo sequences, limiting its capacity to meet the increasing demand for metric ton quantities of oligonucleotides.
Innovation Solution
Liquid phase oligonucleotide synthesis (LPOS) using soluble supports with alkyl chains facilitates homogeneous reaction conditions, enabling efficient conjugation and separation of oligonucleotides, enhancing yield and purity through the use of compounds with suitable functional groups and aliphatic chains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If solid phase oligonucleotide synthesis (SPOS) is used, then simple product isolation and anhydrous synthetic environment are achieved, but low overall yield and high reagent costs occur
Solution Approach 1:
The patent introduces a soluble support compound as an intermediary carrier that temporarily holds the growing oligonucleotide chain during synthesis. This soluble support dissolves in the reaction medium, enabling homogeneous conditions and improved reaction efficiency, while allowing easy removal after synthesis to release the pure oligonucleotide product.
Solution Approach 2:
The patent changes the physical state parameter of the support from solid (insoluble) to soluble by incorporating specific functional groups and hydrophobic alkyl chains. This parameter change enables the support to dissolve in organic solvents, creating homogeneous reaction conditions that improve yield and allow for simpler product isolation through precipitation.
2Ease of manufacture
If solid phase oligonucleotide synthesis (SPOS) is used, then simple product isolation is achieved, but high reagent costs and waste management costs occur
Solution Approach 1:
The patent employs a soluble support compound that can be easily removed and reused or disposed of after a single use. Unlike expensive solid supports that require regeneration or replacement, the soluble support dissolves completely in the reaction medium and can be removed through simple precipitation, reducing overall reagent costs and waste management expenses.
3Ease of manufacture
If solid phase oligonucleotide synthesis (SPOS) is used, then heterogeneous reaction conditions are imposed, but difficulty in purifying mismatched oligo sequences occurs
Solution Approach 1:
The patent employs a soluble support compound that creates homogeneous reaction conditions throughout the synthesis process. The soluble support dissolves in the organic solvent, ensuring uniform distribution of reactants and reagents, which improves the consistency and purity of the oligonucleotide product and facilitates easier purification of mismatched sequences.
4Productivity
If conventional synthesis methods are used, then current production capacity is maintained, but increasing demand for metric ton quantities cannot be met
Solution Approach 1:
The patent divides the oligonucleotide synthesis into discrete, controllable steps using the soluble support system. Each step can be optimized independently, and the soluble support allows for easier scaling up from laboratory to industrial production. The homogeneous conditions and improved yields enable metric ton quantities to be produced efficiently.
Solution Approach 2:
The patent changes the support from solid to soluble state, which fundamentally alters the reaction conditions and enables scalable production. The soluble support allows for improved reaction efficiency, higher yields, and easier product isolation, making it possible to meet the increasing demand for metric ton quantities of oligonucleotides.
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
LPOS provides improved production capacity and purity of oligonucleotides, suitable for multi-kilogram synthesis with good loading capacity and enhanced yield compared to SPOS.
Implementation Method 1
LPOS utilizing soluble supports having alkyl chains is a strategy that may be employed to synthesize oligonucleotides using homogenous reaction conditions
Implementation Method 2
The hydrophobicity of the soluble support having alkyl chains is also compatible with oligonucleotide synthesis, as anhydrous conditions are often required for oligonucleotide chain elongation
Implementation Method 3
contacting a compound described herein in a first solvent with one or more nucleoside analogs to form a first solvent solution comprising a first bioconjugate
Data Source
AI summary
The present disclosure relates to methods and compounds for liquid phase oligonucleotide synthesis employing the use of small molecules with lipophilic groups. Methods for making an oligonucleotide by liquid phase oligonucleotide synthesis using the compounds described herein are also provided.