Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
Codexis, Inc., 200 Penobscot Drive, Redwood City, CA 94063, USA.
Science. 2019 Dec 6;366(6470):1255-1259. doi: 10.1126/science.aay8484.
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.
酶催化反应已开始改变制药行业，提供了更高的选择性和可调性，从而显著改善化学合成。将酶反应组合到多步生物催化级联中会带来更多益处。级联避免了中间产物纯化产生的浪费。它们还可以将反应连接在一起，以克服不利的平衡或避免不稳定或抑制性中间产物的积累。我们报告了一种体外生物催化级联合成研究性 HIV 治疗药物依曲韦林的方法。通过定向进化工程设计了 5 种酶，使其能够作用于非天然底物。将这 5 种酶与 4 种辅助酶结合，以三步生物催化级联的方式从简单的起始原料构建依曲韦林。该总合成所需的步骤数不到先前报道的路线的一半。
