Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19

Molnupiravir (MK-448 2) is an investigational antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand and urgency for this compound, it was critical to develop a short and sustainable synthesis from simple raw materials that would minimize the time needed to manufacture and supply molnupiravir. The route reported here is enabled through the invention of a novel biocatalytic cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase. These engineered enzymes were deployed with a pyruvate-oxidaseenabled phosphate recycling strategy. Compared to the initial route, this synthesis of molnupiravir is 70% shorter and approximately 7-fold higher yielding. Looking forward, the biocatalytic approach to molnupiravir outlined here is anticipated to have broad applications for streamlining the synthesis of nucleosides in general.

Automated summary

To meet the high demand and urgency for the investigational antiviral agent molnupiravir in treating COVID-19, a novel biocatalytic cascade was developed with engineered enzymes to significantly shorten the synthesis time by 70% and increase yield by approximately 7-fold compared to the initial route. This biocatalytic approach is expected to have broad applications for simplifying nucleoside synthesis.