Liquid Phase Oligonucleotide Synthesis

Therapeutic oligonucleotides represent a highly effective drug modality with the potential to treat a wide range of diseases. The increasing number of approved therapies, along with those in advanced clinical trials, will place unprecedented demands on our capacity to manufacture oligonucleotides at scale. Conventional solid phase oligonucleotide synthesis (SPOS), while providing high quality oligonucleotides quickly, suffers from a number of scalability limitations (especially in a lab environment) and high reagent consumption. As an alternative strategy, liquid phase oligonucleotide synthesis (LPOS) has recently received increasing attention.

The term LPOS is employed to differentiate the method in which chemically synthesized oligonucleotides are produced in solution without conventional solid support. It is one approach that holds the potential for becoming the method of choice should demand for metric ton quantities of single or multiple oligonucleotides arise. Unlike SPOS, in LPOS the polymer support is soluble in the organic solvent in which the reaction takes place. This allows the chemical reaction to be accomplished under homogeneous conditions. This homogeneity provides linear reaction kinetic behavior, makes the distribution of reactants more uniform, and makes the reagents more likely to react.

Figure 1. Schematic view of LPOS using soluble supports^[1].

Advantages of Liquid Phase Synthesis

One of the main advantages of LPOS over SPOS is the absence of the heterogeneous nature of the process and the absence of insoluble solid supports. This method also minimizes the need for costly reagents and eliminates the need for excess amidite monomer required to drive the reaction to completion. Additionally, LPOS overcomes the loading capacity limits of solid supports and can be executed in conventional batch reactors, making it more practical for large-scale oligonucleotide production without relying on automated synthesizers. Finally, since the concept of LPOS involves covalently attaching a high molecular weight soluble support to the growing oligonucleotide chain, the product can be easily separated from unreacted reagents and impurities due to the difference in size.

Our Liquid Phase Synthesis Methods

We have developed several methods for the liquid phase synthesis of oligonucleotides using soluble supports instead of solid resins. These methods mainly include:

• PEG-Based Liquid Phase Synthesis

Polyethylene glycol (PEG) is one of the most commonly used soluble polymer supports in LPOS. PEG-based liquid phase synthesis minimizes contamination risks, reduces solvent waste, and enhances process efficiency, making it an ideal choice for the industrial-scale production of oligonucleotides.

• Non-Polymeric Anchor-Assisted Synthesis

Non-polymeric anchor-assisted synthesis includes ionic liquid tag-assisted synthesis, fluorous tag-assisted synthesis, tetravalent cluster approach, adamntylmethylester synthesis, alkyl chain-assisted synthesis, and more.

Related Products

Alfa Chemistry has developed a range of products using LPOS technology, including but not limited to 3'-protected monomers, 5'-DMTr-3'-OH oligomers, 3'-protected oligomers, and 3'-phosphoramidite oligomers. Their representative structural formulas are as follows:

LPOS is a cutting-edge approach to oligonucleotide production with the flexibility and scalability required for modern therapeutic development. Alfa Chemistry is at the forefront of liquid phase synthesis of oligonucleotides. We possess advanced liquid phase synthesis technology and processes, making us a reliable partner for meeting large-scale oligonucleotide production needs. If you have any related needs, please contact us immediately.

Our products and services are for research use only and cannot be used for any clinical purposes.

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