Liquid‐Phase Oligonucleotide Synthesis: Past, Present, and Future Predictions

Abstract

Therapeutic oligonucleotides have emerged as a powerful paradigm with the ability to treat a wide range of the human diseases. As a result, we have witnessed more than one hundred oligonucleotides currently in active clinical trials and eight Food and Drug Administration (FDA)‐approved drugs. Until now, the demand for oligonucleotide‐based drugs has been fulfilled by conventional solid‐phase synthesis in an effective manner. However, there are products in advanced stages of clinical trials projecting a collective demand of metric ton quantities in the near future. Therefore, large‐scale manufacturing of these products has become a high priority for process chemists. This article summarizes the advances in liquid‐phase oligonucleotide synthesis (LPOS) as a possible alternative strategy to meet the scale‐up challenge. A review of the literature describing major efforts in developing LPOS technologies is presented. Gratifyingly, serious attempts are under way to develop an efficient environmentally benign green chemistry protocol that is scalable and cost effective for the manufacturing of oligonucleotides. A summary of the most innovative LPOS protocols has been included to provide a glimpse of what may be possible in the future for large‐scale production of oligonucleotides. © 2019 by John Wiley & Sons, Inc.

Molecular photoswitches in aqueous environments

“…Solid phase peptide and oligonucleotide synthesis have been employed to synthesize known biomolecules with unnatural moieties such as photoswitches and even molecular motors, on a resin by stepwise coupling of each building block. [677][678][679][680] Peptides with a photoswitch in the backbone. Azobenzenes with two biphenyl rings were incorporated via SPPS into a highly water-soluble short peptide chain to study the photochemical behavior of the construct in water (Fig.…”

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing

“…One approach that has seen renewed interest recently is the concept of oligonucleotide synthesis in organic solution, termed LPOS. 64 In this technology, the growing oligonucleotide is attached to a soluble anchor molecule and the reactions are performed in homogeneous solution. Compounds that would interfere with subsequent transformations are removed either by membrane filtration or precipitation after each step.…”

Scalable One-Pot-Liquid-Phase Oligonucleotide Synthesis for Model Network Hydrogels

“…As an alternative strategy, liquid-phase oligonucleotide synthesis (LPOS) uses homogeneous reaction mixtures with, in principle, unlimited scalability, and requires significantly smaller reagent excesses. [41][42] In LPOS, oligonucleotides are grown from a soluble support, which can be separated from the reaction mixture after each step by precipitation, [43][44][45][46][47][48] extraction, 49 chromatography, 50 or nanofiltration. 51 The most prominent of these -the high efficiency liquid-phase (HELP) method -uses a polyethylene glycol (PEG) support, which is precipitated after each step.…”