Molnupiravir (MK-4482) is an investigational direct-acting antiviral agent that is is under development for the treatment of COVID-19. Given the potential high demand for this compound, it was critical to develop a sustainable and efficient synthesis from commodity raw materials. Herein we presented a three-step route including a novel biocatalytic cascade and final condensation step. The key enabler for developing a robust manufacture process is protein engineering of S-methyl-5-thioribose kinase and uridine phosphorylase through directed evolution. Compared to the initial route, the new route is 70% shorter, and approximately seven-fold higher in overall yield.

Invention of an ideal synthesis of molnupiravir enabled by protein engineering

ACS Fall 2021

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