McIntosh John A, Benkovics Tamas, Silverman Steven M, Huffman Mark A, Kong Jongrock, Maligres Peter E, Itoh Tetsuji, Yang Hao, Verma Deeptak, Pan Weilan, Ho Hsing-I, Vroom Jonathan, Knight Anders M, Hurtak Jessica A, Klapars Artis, Fryszkowska Anna, Morris William J, Strotman Neil A, Murphy Grant S, Maloney Kevin M, Fier Patrick S
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Codexis, Inc., 200 Penobscot Drive, Redwood City, California 94063, United States.
ACS Cent Sci. 2021 Dec 22;7(12):1980-1985. doi: 10.1021/acscentsci.1c00608. Epub 2021 Oct 29.
Molnupiravir (MK-4482) 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-oxidase-enabled 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.
莫努匹拉韦（MK-4482）是一种正在研发用于治疗新冠肺炎的抗病毒药物。鉴于对该化合物潜在的高需求和紧迫性，开发一种从简单原料出发的简短且可持续的合成方法至关重要，这将最大限度地减少生产和供应莫努匹拉韦所需的时间。本文报道的合成路线是通过发明一种新型生物催化级联反应实现的，该反应以一种工程化核糖基-1-激酶和尿苷磷酸化酶为特色。这些工程化酶与一种基于丙酮酸氧化酶的磷酸盐循环策略一起使用。与最初的路线相比，莫努匹拉韦的这种合成方法缩短了70%，产率提高了约7倍。展望未来，本文概述的莫努匹拉韦生物催化方法有望在简化核苷合成方面得到广泛应用。
