An Engineered Cytidine Deaminase for Biocatalytic Production of a Key Intermediate of the Covid-19 Antiviral Molnupiravir

• DOI: 10.1021/jacs.1c11048
• Publication Date: 2022-02-28T13:01:00Z
• Authors: Ashleigh J. Burke; William R. Birmin...; Ying Zhuo; Thomas W. Thorpe; Bruna Zucoloto da...; Rebecca Crawshaw; Ian Rowles; James D. Finnigan; Carl Young; Gregory M. Holgate; Mark P. Muldowney; Simon J. Charnock; Sarah L. Lovelock; Nicholas J. Turner; Anthony P. Green
• Keywords: Cytidine; Biocatalysis

The Covid-19 pandemic highlights the urgent need for cost-effective processes to rapidly manufacture antiviral drugs at scale. Here we report a concise biocatalytic process Molnupiravir, nucleoside analogue recently approved as an orally available treatment SARS-CoV-2. Key success of this was development efficient biocatalyst production N-hydroxy-cytidine through evolutionary adaption hydrolytic enzyme cytidine deaminase. This engineered performs >85 000 turnovers in less than 3 h, operates 180 g/L substrate loading, and benefits from situ crystallization product (85% yield), which can be converted Molnupiravir by selective 5′-acylation using Novozym 435.