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。
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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