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Burke et al ChemRxiv manuscript 5 Feb 2021 Final.pdf (353.12 kB)

A Biocatalytic Approach to a Key Intermediate for the Synthesis of the COVID-19 Experimental Drug Molnupiravir

preprint
submitted on 05.02.2021, 16:56 and posted on 08.02.2021, 12:39 by Ashleigh Burke, William Birmingham, Ying Zhuo, Bruna Zuculoto da Costa, Rebecca Crawshaw, Thomas Thorpe, Ian Rowles, James Finnigan, Simon J. Charnock, Sarah Lovelock, Nicholas Turner, Anthony Green
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.

Funding

Bill & Melinda Gates Foundation

History

Email Address of Submitting Author

nicholas.turner@manchester.ac.uk

Institution

University of Manchester

Country

United Kingdom

ORCID For Submitting Author

0000-0002-8708-0781

Declaration of Conflict of Interest

No conflict of interest

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