Polyvalent Hub Oligonucleotide Synthesis Reducing Solvent Waste
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Solution Overview
Problem
Current liquid phase oligonucleotide synthesis technologies face challenges such as high E factor, excessive reagent and solvent usage, and inefficient purification methods, particularly due to the need for costly nanofiltration technologies and difficulties in isolating and purifying oligonucleotides.
Innovation Solution
The use of a polyvalent hub (PVH) with reactive ester groups for efficient conjugation with nucleoside or nucleotide analogs, eliminating the need for succinate linkers and employing regenerated cellulose membranes for cost-effective isolation and purification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If liquid phase oligonucleotide synthesis is employed to increase production capacity, then productivity is improved, but solvent usage and E factor increase
Solution Approach 1:
The patent employs a soluble polymer support that forms a molecular scaffold in liquid phase, enabling oligonucleotide synthesis without insoluble solid supports. This soluble support system allows for efficient product isolation through precipitation or filtration of the polymer-conjugate, significantly reducing solvent consumption compared to traditional liquid phase methods while maintaining high production capacity
Solution Approach 2:
The patent utilizes a polymer support with controlled molecular weight and solubility parameters that enable the synthesis to proceed in liquid phase with reduced solvent requirements. By optimizing the polymer's hydrophobicity and molecular weight, the system achieves efficient product release with minimal solvent washes, addressing the contradiction between productivity and solvent usage
2Manufacturing precision
If nanofiltration technology is used for isolation and purification, then manufacturing precision is improved, but device complexity and cost increase
Solution Approach 1:
The patent employs a soluble polymer support that can be selectively precipitated or filtered from solution, allowing simple isolation of the oligonucleotide product through basic filtration or precipitation techniques. This approach replaces complex nanofiltration membranes with straightforward separation methods, reducing device complexity while maintaining purification efficiency
Solution Approach 2:
The soluble polymer support acts as a disposable scaffold that can be easily removed from the final product. The support is designed to be inexpensive and single-use, eliminating the need for expensive, complex nanofiltration systems while achieving the same purification goal through simple precipitation or filtration of the polymer-conjugate
3Ease of operation
If solid phase oligonucleotide synthesis is used to simplify product isolation, then ease of operation is improved, but productivity and cost effectiveness worsen
Solution Approach 1:
Instead of using insoluble solid supports that require cleavage and extensive washing, the patent inverts the approach by using soluble polymer supports that remain in solution during synthesis. The product is isolated by precipitating or filtering the polymer-conjugate, combining the operational simplicity of solid phase methods with the productivity advantages of liquid phase synthesis
Solution Approach 2:
The soluble polymer support creates a flexible, solution-based scaffold that enables simple product isolation through precipitation or filtration, maintaining ease of operation. Simultaneously, the liquid phase environment allows for higher reaction rates and scalability, improving productivity compared to traditional solid phase methods
4Productivity
If conventional liquid phase synthesis methods are used, then productivity is improved, but purification efficiency worsens due to excessive reagent and solvent usage
Solution Approach 1:
The soluble polymer support forms a concentrated scaffold in solution that maintains high local reagent concentrations for efficient synthesis while enabling simple product isolation. The polymer-conjugate can be precipitated or filtered directly, achieving both high productivity and efficient purification without excessive solvent usage
Solution Approach 2:
The patent optimizes the polymer support's molecular weight and solubility to achieve a balance between maintaining high reaction rates (productivity) and enabling efficient product isolation (purification efficiency). By controlling the polymer's physical parameters, the system achieves concentrated reaction conditions with simple downstream processing
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
This approach enhances the yield and efficiency of oligonucleotide synthesis, reduces solvent usage, and provides a cost-effective alternative for multi-kilogram production by enabling efficient removal of excess reagents and protecting groups.
Implementation Method 1
the PVH comprises or is an acrylate polymer having a plurality of reactive ester groups capable of reacting with nucleoside or nucleotide analogs
Data Source
AI summary
Embodiments of the present application relate to polymers for liquid phase oligonucleotide synthesis. Methods for making an oligonucleotide by liquid phase oligonucleotide synthesis, comprising dissolving a polyvalent hub having a plurality of functional groups in a solvent and contacting the polyvalent hub with one or more nucleoside analogs to form a first bioconjugate are also provided.