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

用于非天然生物催化 C-H 功能化反应的金属酶重编程化学模拟平台

• 批准号: 10661833
• 负责人: Xiongyi Huang
• 金额: $ 39.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661833
• 关键词: Anabolism; Biochemical; Biochemistry; Biological; Biology; Catalysis; Chemicals; Collection; Computer Models; Development; Enzymes; Evolution; Genetic; Hydrogen Bonding; Knowledge; Medicine; Methods; Molecular; Organic Synthesis; Process; Protein Engineering; Proteins; Reaction; Research; System; catalyst; chemical synthesis; drug development; drug discovery; drug synthesis; functional group; metalloenzyme; method development; mimetics; novel therapeutics; programs; small molecule; tool

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

摘要/摘要 分子构建和功能化方法的开发使该药物加快了 在过去几十年中的发展过程。为此，酶C – H功能化代表 强大的方法来快速分子结构。利用有机的无处不在的C – H键 蛋白质催化剂的分子和遗传可鼠，酶C – H功能化可持续 以高选择性和效率实现化学转化的策略。尽管取得了重大进展， 当前酶C – H功能化的反应范围仅限于获得的化学反应率 通过自然进化。这种限制阻碍了酶在药物开发中的应用 在生物学中，很少存在或完全没有药物重要的化学基序。扩展 生物合成的化学空间，我们在这里旨在通过重新利用来开发新的生物催化系统 C -H官能化反应目前不存在生物学中的能力性反应。通过整合蛋白质 工程，计算建模，有机合成以及生物化学和无机光谱 分析，我们将创建可以直接功能化惰性C（SP3）–H的金属酶催化剂的集合 键安装生物医学相关的化学部分。我们设想我们创建的酶不会 仅为众多合成和生物学应用提供有力的遗传编码工具，但会 还提供肥沃的理由来丰富我们对生物化学和酶促催化的基本知识