Molina Alejandro Gimenez, Sanghvi Yogesh S
Nucleic Acid Center, Department of Physics, Chemistry & Pharmacy, University of Southern Denmark, Odense, Denmark.
Rasayan Inc., Encinitas, California.
Curr Protoc Nucleic Acid Chem. 2019 Jun;77(1):e82. doi: 10.1002/cpnc.82. Epub 2019 Mar 28.
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.
治疗性寡核苷酸已成为一种强大的范例，能够治疗多种人类疾病。因此，我们已经看到目前有一百多种寡核苷酸正在进行积极的临床试验，并且有八种药物获得了美国食品药品监督管理局（FDA）的批准。到目前为止，基于寡核苷酸的药物需求已通过传统的固相合成有效地得到满足。然而，处于临床试验后期阶段的产品预计在不久的将来会有公吨级别的集体需求。因此，这些产品的大规模生产已成为工艺化学家的首要任务。本文总结了液相寡核苷酸合成（LPOS）作为应对扩大规模挑战的一种可能替代策略的进展。文中介绍了对描述开发LPOS技术主要努力的文献的综述。令人欣慰的是，正在认真尝试开发一种高效的、对环境无害的绿色化学方案，该方案对于寡核苷酸的制造具有可扩展性且具有成本效益。文中包含了最具创新性的LPOS方案的总结，以展示未来大规模生产寡核苷酸可能实现的情况。© 2019约翰威立父子公司版权所有
