美国默克公司Mark A. Huffman、Anna Fryszkowska等研究人员设计出了体外生物催化级联方案用于islatravir的生产。该项研究成果发表在2019年12月6日出版的《科学》上。

研究人员报告了研究性HIV治疗药物islatravir的体外生物催化级联合成。通过定向进化工程改造了五种酶，使其作用于非天然底物。将它们与四种辅助酶组合，以简单的结构单元以三步生物催化级联方式产生islatravir。整个合成所需的步数比以前报道中的路线少一半。

据介绍，酶催化反应已经开始改变药物的生产，并提供了可大大改善化学合成的选择性和可调性水平。将酶促反应结合到多步生物催化级联反应中可带来更多好处。级联避免了中间体纯化所产生的浪费。它们还能够将反应链接在一起，以克服不利的平衡或避免不稳定或抑制性中间体的积累。

附：英文原文

Title: Design of an in vitro biocatalytic cascade for the manufacture of islatravir

Author: Mark A. Huffman, Anna Fryszkowska, Oscar Alvizo, Margie Borra-Garske, Kevin R. Campos, Keith A. Canada, Paul N. Devine, Da Duan, Jacob H. Forstater, Shane T. Grosser, Holst M. Halsey, Gregory J. Hughes, Junyong Jo, Leo A. Joyce, Joshua N. Kolev, Jack Liang, Kevin M. Maloney, Benjamin F. Mann, Nicholas M. Marshall, Mark McLaughlin, Jeffrey C. Moore, Grant S. Murphy, Christopher C. Nawrat, Jovana Nazor, Scott Novick, Niki R. Patel, Agustina Rodriguez-Granillo, Sandra A. Robaire, Edward C. Sherer, Matthew D. Truppo, Aaron M. Whittaker, Deeptak Verma, Li Xiao, Yingju Xu, Hao Yang

Issue&Volume: 2019/12/06

Abstract: Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.

DOI: 10.1126/science.aay8484

Source:https://science.sciencemag.org/content/366/6470/1255