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:
- 金额:$ 6.49万
- 依托单位:
- 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:
- 关键词:AcylationAffectAlcoholsAldehydesAlkenesAmidesAminesAmino Acid SubstitutionAnhydridesAromatic CompoundsBiologicalBiological ProcessBiologyCatalysisChemicalsCollectionComplexCouplingDependenceDetectionDimethyl SulfoxideDirected Molecular EvolutionDiseaseDrug CompoundingEffectivenessEngineeringEnzymesEstersExhibitsFamilyFlavinsFutureGoalsGrantHumanKnowledgeLibrariesLifeMethodsMolecularMutagenesisNatural ProductsOrganic solvent productOutcomePathway interactionsPatientsPharmaceutical PreparationsPhilosophyProceduresProcessPropertyReactionReagentResearchRing CompoundRouteSiteSolubilitySolventsSpecificityStructureSystemTechniquesVariantWalkingcarboxylatecarboxylationcatalystcofactorcostcost effectivedesigndrug developmentdrug discoverydrug synthesisenantiomerhigh throughput screeninghuman diseaseimprovedmutantnon-Nativenovelpotassium bicarbonatescaffoldscreeningside effectsmall moleculestereochemistrytechnique developmentthermophilic organismtool
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.
项目摘要/摘要
具有良好生物学性质的小分子的发现和合成具有显著的
提高了人类的生活质量。然而,目前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,这些反应经常只对
期望的结果。近年来,酶越来越多地与合成反应结合使用。
生产的产品具有无与伦比的选择性,且不需要有害溶剂。工程新闻
用于新反应的酶平台将扩大对药物有利的生物催化剂的集合
因此,这是一个值得追求的目标。
定向进化已被证明是开发酶的一种无与伦比的技术,展示了
对一系列所需反应具有极佳的催化能力。从P450到TrpB酶,许多
天然支架已经被进化来有效地催化生物学上已知的和新的反应
扩展我们的合成工具箱。
本文提出的研究目的是通过定向进化来设计PrFMN(PrFMN)酶
产生生物催化剂,为更具成本效益的药物化合物铺平道路
人类疾病的治疗。为此,将先前表征的prFMN酶应用于非
天然C-C偶联反应,最终生成手性烯丙醇和芳香醇。这种化学物质
在许多药物支架中都发现了部分;然而,目前的合成过程往往不充分。
对产品立体化学的控制。第二个目标是将prFMN酶应用于芳香族酰化反应。
反应,类似于上述的C-C偶联反应,将导致不同和复杂的分子
脚手架。设计新的合成途径以获得复杂和多样化的环结构对药物很重要
发现过程由以多样性为导向的哲学综合。第三个目标是重定向本机
PrFMN对大的含环化合物的芳香族羧化的反应性。后期羧化
复杂的分子支架可以提供另一个支点来产生复杂和多样化的文库
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
设计能够高度催化化学转化的酶变异体
专一性。这里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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nature's Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases.
自然的机械,重新利用:扩展铁依赖性氧酶的曲目。
- DOI:10.1021/acscatal.0c03606
- 发表时间:2020-10-16
- 期刊:
- 影响因子:12.9
- 作者:Dunham NP;Arnold FH
- 通讯作者:Arnold FH
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