Pseudo Solid-Phase Protecting Groups for Oligonucleotide Scale-Up
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Solution Overview
Problem
Existing solid-phase synthesis processes for oligonucleotides face challenges in scalability due to excessive reagent consumption and difficulty in monitoring reaction progress and analyzing intermediate structures, while liquid-phase synthesis using pseudo solid phase protecting groups requires improvements for simplicity and cost-efficiency.
Innovation Solution
Development of novel pseudo solid phase protecting groups that are simple to produce, avoid premature cleavage, and allow complete cleavage under suitable conditions, facilitating oligonucleotide synthesis with soluble supports.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If solid-phase synthesis is used for oligonucleotide production, then synthesis speed and automation are improved, but reagent consumption increases excessively and scalability becomes difficult
Solution Approach 1:
The patent introduces a soluble support (pseudo solid phase protecting group) as an intermediary carrier that enables liquid-phase synthesis. This mediator allows the oligonucleotide to be synthesized in solution rather than on a solid support, facilitating easier reagent management and scalability while maintaining synthesis efficiency. The soluble support acts as a temporary carrier that can be easily removed after synthesis.
Solution Approach 2:
The patent changes the physical state parameter of the synthesis medium from solid-phase to liquid-phase by using a soluble support. This parameter change enables the synthesis to proceed in solution, improving reagent consumption efficiency and scalability while maintaining the speed advantage of automated synthesis through liquid handling systems.
2Extent of automation
If solid-phase synthesis is used for oligonucleotide production, then automated synthesis is enabled, but real-time reaction monitoring and intermediate structure analysis become difficult
Solution Approach 1:
The soluble support serves as an intermediary that allows the oligonucleotide to remain in solution throughout the synthesis process. This enables real-time monitoring of reaction progress and intermediate structures through various analytical techniques (NMR, MS, HPLC) that would be difficult or impossible with solid-phase synthesis. The solution-phase intermediate can be easily accessed and analyzed without solid support interference.
3Ease of operation
If existing pseudo solid phase protecting groups are used, then liquid-phase synthesis is enabled, but production complexity and cost increase
Solution Approach 1:
The patent employs a soluble support that is simple, cost-effective, and easily removable. This disposable-like approach uses a straightforward chemical structure (pseudo solid phase protecting group) that can be introduced and removed without complex equipment or procedures. The soluble support is designed to be inexpensive and can be cleaved under mild conditions, reducing overall production complexity and cost compared to existing alternatives.
4Ease of operation
If existing pseudo solid phase protecting groups are used, then liquid-phase synthesis is enabled, but premature cleavage occurs and toxic heavy metals or hydrogen gas are required
Solution Approach 1:
The patent changes the chemical parameters of the protecting group to enable selective cleavage under mild, non-toxic conditions. The soluble support is designed with specific functional groups that can be removed using safe reagents (e.g., base treatment) rather than toxic heavy metals or hydrogen gas. This parameter change in the protecting group chemistry eliminates harmful factors while maintaining liquid-phase synthesis capability.
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 protecting groups enable efficient and cost-effective oligonucleotide synthesis by improving scalability and reaction monitoring, reducing reagent consumption, and enabling selective cleavage without toxic heavy metals or hydrogen gas.
Implementation Method 1
Such a hydrophobic group can be selectively cleaved via hydrogenation from oligonucleotides bearing 5′-DMTr, 2-CE, and/or 2′-TBS groups.
Data Source
AI summary
A novel pseudo solid phase protecting group and methods for the synthesis of oligonucleotides and oligonucleotide conjugates are provided. The pseudo solid phase protecting group is represented by formula II wherein: * indicates the point of attachment to an oxygen atom of a hydroxyl moiety of the nucleoside, the nucleotide, the oligonucleotide, or of the conjugate of a nucleoside, a nucleotide or an oligonucleotide to be protected; c is 0 or 1; a is an integer of 1 to 12; R3 is H; R5 is O—R6 or H, where R6 is a C8-C40 aliphatic hydrocarbon group; each of R4 is independently O—R6, where R6 is at each occurrence independently a C8-C40 aliphatic hydrocarbon group; b is 1 to 3; with the proviso that if b is 1, at least one of R3 and R5 is not H; and with the further proviso that the sum of all carbon atoms contained in the R3, R4, and R5 moieties present is larger than 23 and smaller than 200.