Non-Cleavable Amide Linker for High-Purity Nucleic Acid Synthesis
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Solution Overview
Problem
Existing solid-phase nucleic acid synthesis methods face challenges such as low efficiency in cleavage of oligonucleic acids from solid-phase carriers and the production of by-products derived from non-nucleoside linkers, making it difficult to achieve high purity and separation of the target product.
Innovation Solution
A novel universal support is developed with a linker for nucleic acid synthesis that utilizes a non-cleavable amide bond between the solid-phase carrier and linker structure, avoiding the use of conventional cleavable ester bonds, thereby reducing the production of by-products and enhancing the efficiency and purity of nucleic acid synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If a cleavable linker (ester bond) is used between the solid-phase carrier and nucleoside, then the oligonucleic acid can be released from the carrier, but by-products are produced that are difficult to separate from the target product
Solution Approach 1:
The invention extracts and removes the problematic cleavable linker component from the system. Instead of using a cleavable ester bond between the carrier and nucleoside, the patent employs a non-cleavable amide bond, effectively taking out the source of by-product formation while maintaining the essential function of oligonucleic acid synthesis and release
Solution Approach 2:
The invention changes the chemical nature of the bond between the carrier and nucleoside from a cleavable ester bond to a non-cleavable amide bond. This parameter change in bond stability and chemistry eliminates the formation of linker-derived by-products during the cleavage process, while the oligonucleic acid can still be released through alternative mechanisms
2Adaptability or versatility
If a universal support with non-nucleoside linker is used, then all nucleic acid sequences can be synthesized using a single carrier, but the cleavage efficiency is low
Solution Approach 1:
The invention changes the bond type parameter from ester to amide, which fundamentally alters the cleavage mechanism and efficiency. The amide bond provides stability during synthesis while allowing for efficient release under appropriate conditions, thereby improving productivity without sacrificing the universal adaptability of the carrier system
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
The new linker and carrier system allows for high-purity nucleic acid synthesis with improved efficiency by promoting nucleophilic attack on the phosphate group, ensuring efficient release from the solid-phase carrier and minimizing the formation of linker adducts.
Implementation Method 1
subjecting a compound represented by the following formula (1) to an oxidation reaction in a solvent in the presence of an oxidizing agent and a reoxidizing agent
Implementation Method 2
promoting nucleophilic attack on the phosphate group, ensuring efficient release from the solid-phase carrier
Data Source
AI summary
An object of the present invention is to newly provide a linker for nucleic acid synthesis and a carrier for solid-phase nucleic acid synthesis. Provided are a linker precursor for nucleic acid synthesis, a linker for nucleic acid synthesis, and a carrier for solid-phase nucleic acid synthesis.