Abstract
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.