Journal
ACS CENTRAL SCIENCE
Volume 7, Issue 12, Pages 1980-1985Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.1c00608
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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.
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.
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