Liquid‐Phase Synthesis of 2′‐Methyl‐RNA on a Homostar Support through Organic‐Solvent Nanofiltration

Gaffney, Piers R. J.; Kim, Jeong F.; Valtcheva, Irina B.; Williams, Glynn D.; Anson, M.; Buswell, Andrew M.; Livingston, Andrew G.

doi:10.1002/chem.201501001

Cited by 21 publications

(29 citation statements)

References 45 publications

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“…Overview of Livingston's strategy for OSN‐based LPOS on a PEG soluble support (Gaffney et al., ; Kim et al., ).…”

Section: Overview Of Liquid‐phase Oligonucleotide Synthesis (Lpos)mentioning

confidence: 99%

“…Two protocols, namely high efficiency liquid phase (HELP; Bonora, Scremin, Colonna, & Garbesi, 1990) and HELP Plus (Bonora, Biancotto, Maffini, & Scremin, 1993) enabled gram-scale synthesis of ONs while reducing the overall process time. More recently, Livingston's group (Gaffney et al, 2015;Kim et al, 2016) utilized PEG as a soluble polymer in combination with novel organic solvent nanofiltration (OSN) technology. OSN facilitated the separation of the growing oligomer from excess reagents and impurities via a diafiltration technique during each step of ON synthesis.…”

Section: Historical Perspectivementioning

confidence: 99%

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

Molina

Sanghvi²

2019

CP Nucleic Acid Chemistry

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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.

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“…Overview of Livingston's strategy for OSN‐based LPOS on a PEG soluble support (Gaffney et al., ; Kim et al., ).…”

Section: Overview Of Liquid‐phase Oligonucleotide Synthesis (Lpos)mentioning

confidence: 99%

Section: Historical Perspectivementioning

confidence: 99%

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

Molina

Sanghvi²

2019

CP Nucleic Acid Chemistry

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“…The HELP synthesis requires precipitation to remove unreacted phosphoramidites and other residues at each synthetic step, making it labor intensive. Livingston et al later improved the liquid-phase synthesis by developing an organic solvent nanofiltration (OSN) strategy, which involves a membrane process capable of separating growing PEG-ONs from small-molecule residues [69–71]. The OSN method has the potential to be automated for very large-scale synthesis (possibly > 100 kg, although not yet attempted).…”

Section: Pegylation Of Ons Using Linear or Slightly Branched Pegmentioning

confidence: 99%

PEGylation of therapeutic oligonucletides: From linear to highly branched PEG architectures

Zhang

2018

Nano Res.

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PEGylation, the attachment of poly(ethylene glycol) (PEG), has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the investigation of linear or slightly branched PEG having different molecular weights, terminal functional groups, and possible oligonucleotide sites for functionalization. Recent studies on highly branched PEG (including brush, star, and micellar structures) indicate superior properties in several areas including cellular uptake, gene regulation efficacy, reduction of side effects, and biodistribution. This review focuses on comparing the effects of PEG architecture on the physiochemical and biological properties of the PEGylated oligonucleotide.

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“…The chemical synthetic procedures used in this study are described in full elsewhere 25 . The methods are summarized briefly below.…”

Section: Overall Process and Oligonucleotide Synthesis Chemistrymentioning

confidence: 99%

“…Building on this earlier experience, we have reported the application of OSN purification to LPOS, henceforth a process termed LPOS-OSN 25 . Using the LPOS-OSN process, we have successfully synthesized 5-mer and 9-mer 2'-O-methyl phosphorothioate oligoribonucleotides.…”

Section: Introductionmentioning

confidence: 99%

Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

Kim

Gaffney

Valtcheva

et al. 2016

Org. Process Res. Dev.

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Organic Solvent Nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterative synthesis platform, for instance for oligonucleotides or peptides, where a thorough purification step is required after each synthesis cycle, preferably in the same working solvent. In this work, we report a process development study for liquid-phase oligonucleotide synthesis (LPOS) using OSN technology. Oligonucleotide (oligo) based drugs are being advanced as a new generation of therapeutics functioning at the protein expression level. Currently, over one hundred oligo based drugs are undergoing clinical trials, suggesting that it will soon be necessary to produce oligos at a scale of metric tons per year. However, there are as yet no synthesis platforms that can manufacture oligos at >10 kg batch-scale. With the process developed here, we have successfully carried out 8 iterative cycles of chain extension and synthesized 5-mer and 9-mer 2'-O-methyl oligoribonucleotide phosphorothioates, all in liquid phase media. This paper discusses the key challenges, both anticipated and unexpected, faced during development of this process, and suggests solutions to reduce the development period. An economic analysis has been carried out, highlighting the potential competitiveness of the LPOS-OSN process, and the necessity for a solvent recovery unit.

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Liquid‐Phase Synthesis of 2′‐Methyl‐RNA on a Homostar Support through Organic‐Solvent Nanofiltration

Cited by 21 publications

References 45 publications

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

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

PEGylation of therapeutic oligonucletides: From linear to highly branched PEG architectures

Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

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