Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
Prozomix Ltd, Building 4, West End Ind. Estate, Haltwhistle NE49 9HA, U.K.
J Am Chem Soc. 2022 Mar 9;144(9):3761-3765. doi: 10.1021/jacs.1c11048. Epub 2022 Feb 28.
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 for Molnupiravir, a nucleoside analogue recently approved as an orally available treatment for SARS-CoV-2. Key to the success of this process was the development of an efficient biocatalyst for the production of -hydroxy-cytidine through evolutionary adaption of the hydrolytic enzyme cytidine deaminase. This engineered biocatalyst performs >85 000 turnovers in less than 3 h, operates at 180 g/L substrate loading, and benefits from in situ crystallization of the -hydroxy-cytidine product (85% yield), which can be converted to Molnupiravir by a selective 5'-acylation using Novozym 435.
Covid-19 大流行凸显了以具有成本效益的方式大规模快速生产抗病毒药物的迫切需求。在这里，我们报告了一种用于 Molnupiravir 的简洁生物催化工艺，Molnupiravir 是一种最近被批准用于治疗 SARS-CoV-2 的口服药物。该工艺成功的关键是通过对水解酶胞苷脱氨酶进行进化适应，开发出一种用于生产-β羟基胞苷的高效生物催化剂。这种工程化的生物催化剂在不到 3 小时内进行了>85,000 次周转，在 180 g/L 底物负荷下运行，并受益于-β羟基胞苷产物的原位结晶（85%产率），通过使用 Novozym 435 进行选择性 5'-酰化可以将其转化为 Molnupiravir。
