Biocatalytic Synthesis of Antiviral Nucleosides, Cyclic Dinucleotides, and Oligonucleotide Therapies.
Biocatalytic Synthesis of Antiviral Nucleosides, Cyclic Dinucleotides, and Oligonucleotide Therapies.
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DOI：
10.1021/jacsau.2c00481
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发表时间：
2023-01-23
期刊：
影响因子：
8
通讯作者：
Lovelock, Sarah L
中科院分区：
文献类型：
--
作者：
Van Giesen, Kyle J D;Thompson, Matthew J;Meng, Qinglong;Lovelock, Sarah L
核苷、核苷酸和寡核苷酸调节从蛋白质生产到细胞信号传导的各种细胞过程。因此，核苷及其衍生物的合成类似物作为一种多用途的药物分子出现，用于治疗各种疾病领域，就不足为奇了。尽管它们具有巨大的治疗潜力，但在核酸类似物中存在的密集的官能团和立体中心构成了相当大的合成挑战，特别是在大规模制造的背景下。常用的合成方法依赖于广泛的保护群操作，这损害了步骤经济并导致高过程质量强度。生物催化方法有可能解决这些限制，使开发更精简，选择性和可持续的合成路线成为可能。在这里，我们回顾了最近在核苷和环二核苷酸的生物催化制造方面的成就，以及在开发酶促生产寡核苷酸疗法方面的进展。我们还强调了促进这些生物催化方法在整个制药行业广泛采用所需的创新机会。
Nucleosides, nucleotides, and oligonucleotides modulate diverse cellular processes ranging from protein production to cell signaling. It is therefore unsurprising that synthetic analogues of nucleosides and their derivatives have emerged as a versatile class of drug molecules for the treatment of a wide range of disease areas. Despite their great therapeutic potential, the dense arrangements of functional groups and stereogenic centers present in nucleic acid analogues pose a considerable synthetic challenge, especially in the context of large-scale manufacturing. Commonly employed synthetic methods rely on extensive protecting group manipulations, which compromise step-economy and result in high process mass intensities. Biocatalytic approaches have the potential to address these limitations, enabling the development of more streamlined, selective, and sustainable synthetic routes. Here we review recent achievements in the biocatalytic manufacturing of nucleosides and cyclic dinucleotides along with progress in developing enzymatic strategies to produce oligonucleotide therapies. We also highlight opportunities for innovations that are needed to facilitate widespread adoption of these biocatalytic methods across the pharmaceutical industry.