A Chemo-Mimetic Platform to Reprogram Metalloenzymes for Non-Natural Biocatalytic C-H Functionalization Reactions

摘要/概要 分子构建和功能化方法的发展加快了药物的开发 过去几十年的发展过程。为此，酶促C-H官能化代表了一种新的方法。 强大的方法，使快速分子构建。利用有机化合物中普遍存在的C-H键 分子和蛋白质催化剂的遗传可调性，酶促C-H官能化提供了可持续的 高选择性和高效率的化学转化策略。尽管取得了重大进展， 目前酶促C-H官能化的反应范围限于获得的化学反应性 通过自然进化。这种限制阻碍了酶在药物开发中的应用， 医学上重要的化学基序在生物学中很少存在或甚至完全不存在。扩大 生物合成的化学空间，我们在此旨在通过重新利用 金属酶的C-H官能化反应目前不存在于生物学。通过整合蛋白质 工程、计算建模、有机合成、生物化学和无机光谱 分析，我们将创建金属酶催化剂的集合，可以直接功能化惰性C（sp3）-H 键来安装生物医学相关的化学部分。我们设想我们创造的酶不会 它只为许多合成和生物应用提供了强大的遗传编码工具， 也为丰富我们的生物化学和酶催化的基础知识提供了肥沃的土壤

Abstract/Summary The development of methods for molecule construction and functionalization has expedited the drug development process during the past decades. To this end, enzymatic C–H functionalization represents a powerful approach to enable rapid molecular construction. Harnessing the ubiquitous C–H bonds in organic molecules and genetic tunability of protein catalysts, enzymatic C–H functionalization provides sustainable strategies to effect chemical transformations with high selectivity and efficiency. Despite significant advances, the reaction scope of current enzymatic C–H functionalization is restricted to chemical reactivities acquired through natural evolution. This limitation hampers the applications of enzymes for drug development as many medicinally important chemical motifs are rarely present or even completely absent in biology. To expand the chemical space of biosynthesis, we herein aim to develop new biocatalytic systems by repurposing metalloenzymes for C–H functionalization reactions currently not present in biology. By integrating protein engineering, computational modeling, organic synthesis, and biochemical and inorganic spectroscopic analysis, we will create collections of metalloenzyme catalysts that can directly functionalize inert C(sp3)–H bonds to install biomedically relevant chemical moieties. We envision that the enzymes we create will not only provide powerful genetically encoded tools for numerous synthetic and biological applications, but will also offer a fertile ground to enrich our fundamental knowledge of biochemistry and enzymatic catalysis