Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues

Nucleoside analogues represent a cornerstone of achievement in drug discovery, rising to prominence particularly in the fields of antiviral and anticancer discovery over the last 60 years. Traditionally accessed using chemical synthesis, a paradigm shift to include the use of biocatalytic synthesis is now apparent.

Herein, the authors discuss the recent advances using this technology to access nucleoside analogues. Two key aspects are covered, the first surrounding methodology concepts, effectively using enzymes to access diverse nucleoside analogue space and also for producing key building blocks. The second focuses on the use of biocatalytic cascades for de novo syntheses of nucleoside analogue drugs. Finally, recent advances in technologies for effecting enzymatic nucleoside synthesis are considered, chiefly immobilization and flow.

Enzymatic synthesis of nucleoside analogues is maturing but has yet to usurp chemical synthesis as a first-hand synthesis technology, with scalability and substrate modification primary issues. Moving forward, tandem approaches that harness expertise across molecular microbiology and chemical synthesis will be vital to unlocking the potential of next generation nucleoside analogue drug discovery.