Biocatalytic cascade transformations for the synthesis of C-nucleosides and N-nucleoside analogs

Nucleosides and their analogs, including those that feature substitution of the canonical N-glycosidic by a C-glycosidic linkage, provide access to potent antiviral, antibacterial, and antitumor drugs. Furthermore, they are key building blocks of m-RNA vaccines and play a crucial role for vaccine therapeutic effectiveness. As the medicinal applications of nucleosides increase in number and importance, there is a growing need for efficiency-enhanced routes of nucleoside synthesis. Cascade biocatalysis, that is, the application of natural or evolved enzymes promoting complex transformations in multiple steps in one pot and without the need of intermediate purification, emerges as a powerful tool to obtain nucleosides from readily available starting materials. Recent efforts in enzyme discovery and protein engineering expand the toolbox of catalysts active toward nucleosides or nucleotides. In this review, we highlight recent applications, and discuss challenges, of cascade biocatalysis for nucleoside synthesis. We focus on C-nucleosides and important analogs of the canonical N-nucleosides.