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发展加速了药物的发展 过去几十年的发展进程。为此，酶促C-H官能化代表了一种 能够快速构建分子的强大方法。利用有机化合物中普遍存在的C-H键 蛋白质催化剂的分子和遗传可调性，酶C-H官能化提供了可持续的 以高选择性和高效率实现化学转化的策略。尽管取得了重大进展， 目前的酶C-H官能化反应范围仅限于获得的化学反应活性 通过自然进化。这一限制阻碍了许多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，甚至完全不存在。要扩展 生物合成的化学空间，我们的目标是通过改变用途来开发新的生物催化系统 用于C-H官能化反应的金属酶目前还不存在于生物学中。通过整合蛋白质 工程、计算模型、有机合成、生化和无机光谱 分析，我们将创造一系列金属酶催化剂，可以直接使惰性C(SP3)-H官能化 用于安装与生物医学相关的化学部分的键。我们设想我们创造的酶将不会 只为众多合成和生物应用提供强大的基因编码工具，但将 也提供了丰富我们生物化学和酶催化基础知识的肥沃土壤