A Biocatalytic Approach to a Key Intermediate for the Synthesis of the COVID-19 Experimental Drug Molnupiravir
semanticscholar(2021)
摘要
Herein we report the conversion of cytidine 2 to N-hydroxycytidine 7 catalysed by cytidine deaminase (CD). The wild-type
enzyme operates efficiently at high sustrate loadings and
hydroxylamine concentrations to favor N-hydroxy-cytidine formation
over uridine. Although the wild-type enzyme demonstrated good
activity, we were able to further enhance the ratio of N-hydroxycytidine to uridine produced through directed evolution of CD. In
particular, a T123G mutation close to the active site dramatically
reduces cytidine hydrolysis activity whilst preserving desired
amination activty. The approach reported provides a new route to a
key intermediate for the COVID-19 experimental drug Molnupiravir 1.
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