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Prenylated-Flavin Enzymes as a new Platform for Drug Synthesis and Discovery

异戊二烯化黄素酶作为药物合成和发现的新平台

基本信息

批准号：
9982049
负责人：
Noah Paul Dunham
金额：
$ 6.49万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982049
关键词：
Acylation Affect Alcohols Aldehydes Alkenes Amides Amines Amino Acid Substitution Anhydrides Aromatic Compounds Biological Biological Process Biology Catalysis Chemicals Collection Complex Coupling Dependence Detection Dimethyl Sulfoxide Directed Molecular Evolution Disease Drug Compounding Effectiveness Engineering Enzymes Esters Exhibits Family Flavins Future Goals Grant Human Knowledge Libraries Life Methods Molecular Mutagenesis Natural Products Organic solvent product Outcome Pathway interactions Patients Pharmaceutical Preparations Philosophy Procedures Process Property Reaction Reagent Research Ring Compound Route Site Solubility Solvents Specificity Structure System Techniques Variant Walking carboxylate carboxylation catalyst cofactor cost cost effective design drug development drug discovery drug synthesis enantiomer high throughput screening human disease improved mutant non-Native novel potassium bicarbonate scaffold screening side effect small molecule stereochemistry technique development thermophilic organism tool

项目摘要

Project Summary/Abstract The discovery and synthesis of small molecules that possess favorable biological properties have markedly enhanced the quality of human life. Current methods for the synthesis of these drug compounds, however, rely heavily on environmentally-harsh solvents and reactions that frequently offer only limited selectivity for the desired outcome. In recent years, enzymes have been increasingly used in conjunction with synthetic reactions to yield products with unparalleled selectivity and without the necessity of harmful solvents. Engineering new enzyme platforms for novel reactivity will expand the collection of biocatalysts that are beneficial to the drug development process, and is thus a goal worth pursuing. Directed evolution has proved to be an unrivaled technique for the development of enzymes that exhibit exquisite catalytic capabilities toward an array of desired reactions. From P450s to TrpB enzymes, many natural scaffolds have been evolved to catalyze reactions that are both known and new to biology, effectively expanding our synthetic toolbox. The research proposed herein aims to engineer prenylated-flavin (prFMN) enzymes by directed evolution to generate biocatalysts that can pave the way to more cost-effective avenues to drug compounds used for the treatment of human diseases. To this end, previously-characterized prFMN enzymes will be applied to a non- native C–C coupling reaction that will ultimately produce chiral allylic and aromatic alcohols. This chemical moiety is found in numerous drug scaffolds; however, the current synthetic procedures often grant insufficient control over the product stereochemistry. A second objective is to apply prFMN enzymes to aromatic acylation reactions, a similar C–C coupling reaction described above that will result in diverse and complex molecular scaffolds. Crafting new synthetic avenues to complex and diversifiable ring structures is important to the drug discovery process by the philosophy of diversity-oriented synthesis. A third objective is to redirect the native prFMN reactivity toward the aromatic carboxylation of large, ring-bearing compounds. Late-stage carboxylation of complex molecular scaffolds can provide another branchpoint to produce libraries of complex and diverse molecules for bioactivity screening and drug discovery. Directed evolution will be applied throughout each aim to engineer enzyme variants capable of catalyzing the chemical transformations with a high degree of specificity. The biocatalysts developed herein may also serve as a platform for future engineering endeavors involving the prFMN cofactor.

项目总结/摘要具有良好生物学特性的小分子的发现和合成具有显著的生物学特性。提高了人类的生活质量。然而，目前用于合成这些药物化合物的方法依赖于严重依赖于环境苛刻的溶剂和反应，这些溶剂和反应通常仅提供有限的选择性，期望的结果。近年来，酶越来越多地与合成反应结合使用以无与伦比的选择性和不需要有害溶剂的条件得到产物。设计新用于新反应性的酶平台将扩大对药物有益的生物催化剂的收集这是一个值得追求的目标。定向进化已被证明是一种无与伦比的技术，用于开发酶，对一系列所需反应的精细催化能力。从P450到TrpB酶，天然支架已经进化成有效地催化生物学已知和新的反应，扩大我们的合成工具箱本文提出的研究旨在通过定向进化来工程化异戊烯基化黄素（prFMN）酶产生生物催化剂，可以铺平道路，以更具成本效益的途径，以药物化合物用于治疗人类疾病。为此，先前表征的prFMN酶将应用于非- 天然C-C偶联反应，最终产生手性烯丙基和芳香醇。这种化学在许多药物支架中发现了半胱氨酸;然而，目前的合成方法通常不足以控制产物的立体化学。第二个目的是将prFMN酶应用于芳族酰化反应，类似于上述的C-C偶联反应，其将导致不同的和复杂的分子结构。脚手架对于这种药物来说，创造新的合成途径以获得复杂和多样化的环结构是很重要的。发现过程的哲学多样性为导向的综合。第三个目标是重新引导本地人 prFMN对大的、带环的化合物的芳族羧化的反应性。后期羧化可以提供另一个分支点，以产生复杂和多样的用于生物活性筛选和药物发现的分子。定向进化将应用于每个目标为了工程化能够以高度的生物相容性催化化学转化的酶变体，的特异性本文开发的生物催化剂也可以作为未来工程努力的平台涉及prFMN辅因子。