Development of a Biocatalytic Platform for Convergent Synthesis of Chiral Amines

手性胺聚合合成生物催化平台的开发

• 批准号: 9908105
• 负责人: FRANCES H ARNOLD
• 金额: $ 29.19万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908105
• 关键词: Acrylates; Active Sites; Address; Aldehyde-Lyases; Amines; Amino Acids; Amino Alcohols; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Binding; Biological; Branched-Chain Amino Acids; Carbon; Complex; Dehydration; Development; Diagnosis; Directed Molecular Evolution; Engineering; Environment; Enzymes; Health; Homoserine; Human; Indoles; Industry; Machine Learning; Mediating; Nature; Pharmacologic Substance; Physical condensation; Population; Process; Production; Propanolamines; Property; Protein Engineering; Pyridoxal Phosphate; Reaction; Reagent; Research; Route; Solvents; Synthesis Chemistry; Threonine; Transaminases; Tryptophan Synthase; Tweens; Variant; Work; analog; base; carboxylate; catalyst; chemical synthesis; cofactor; design; drug discovery; drug production; empowered; enzyme activity; human disease; improved; interest; novel; novel lead compound; serine containing aminolipid; serinol; success; thermostability; tool

Project Abstract The protection of human health depends on the continued discovery of biologically active compounds and their development into useful pharmaceuticals. Historically, synthetic chemistry has enabled medicinal chemists to create and optimize novel lead compounds and has empowered process chemists to produce compounds at the scale necessary for the treatment of a population. The processes of drug discovery and drug production are undergoing a dramatic change with the development of efficient enzyme catalysts as practical tools for synthesis. Medicinal chemists are now harnessing the promiscuous activities of enzymes to access in a single step medicinally relevant compounds that otherwise require multiple-step chemical syntheses. Further, process chemists are starting to leverage the unrivalled efficiency and inherent sustain- ability of enzymes to replace the expensive catalysts and the toxic reagents and solvents that characterize many current production routes. As a result, enzymes are rapidly becoming important tools for pharmaceu- tical synthesis. These transformative developments are unfortunately limited by the relative dearth of useful synthetic reactions in the ‘biocatalytic toolbox’. Our group has made fundamental advances to expanding this toolbox by using directed evolution to obtain new, useful biocatalysts starting from enzymes whose activities may have been low or even undetectable for the desired substrate or reaction. This proposal seeks to expand and generalize a powerful biocatalytic platform for the synthesis of chiral amines. Such compounds are prevalent as building blocks for pharmaceuticals that encompass all realms of human health such as antibacterial, antifungal, and anticancer drugs. The ability to improve upon these compounds is dependent on access to suitable building blocks. We have identified the enzyme TrpB as a unique biocatalyst for the synthesis of chiral amines. This enzyme mediates a bond-forming reaction be- tween two substrates, one nucleophilic and one electrophilic. Previous work has almost exclusively focused on the activity of this enzyme with diverse nucleophilic substrates, for which TrpB has modest promiscuity. The research proposed here, by contrast, aims to expand the electrophilic substrate scope of the enzyme to make highly functionalized α-amino acids, as well as other classes of chiral amine such as amino alcohols and β-amino acids. The result of this research will be a new suite of biocatalysts that can be used to syn- thesize a wide range of chiral amine building blocks for the novel medicinal compounds essential for ad- vancing the diagnosis and treatment of human diseases.

项目摘要 人类健康的保护依赖于生物活性化合物的不断发现 以及将其开发成有用的药物。从历史上看，合成化学使药物 化学家创造和优化新的先导化合物，并授权工艺化学家生产 以治疗人群所需的规模生产化合物。药物发现的过程， 随着高效酶催化剂的发展，药物生产正在经历一场戏剧性的变革， 合成的实用工具。药物化学家现在正在利用酶的混杂活性 为了在单一步骤中获得医学上相关的化合物， 合成。此外，工艺化学家开始利用无与伦比的效率和固有的持续性， 酶的能力，以取代昂贵的催化剂和有毒的试剂和溶剂的特点， 目前的许多生产线。因此，酶正迅速成为制药业的重要工具。 化学合成 不幸的是，这些变革性的发展受到有用的合成药物相对缺乏的限制。 在“生物催化工具箱”中进行反应。我们的团队在扩展这个工具箱方面取得了根本性的进展 通过使用定向进化来获得新的、有用的生物催化剂， 对于所需的底物或反应来说是低的或甚至是不可检测的。 该建议旨在扩展和推广一个强大的生物催化平台，用于合成手性 胺。这些化合物普遍用作涵盖所有领域的药物的构建块 抗细菌、抗真菌和抗癌药物等对人体健康的影响。改善这些的能力 化合物的制备依赖于获得合适的结构单元。我们已经确定TrpB酶是一种 合成手性胺的独特生物催化剂。这种酶介导一种键形成反应， 在两种底物之间，一种亲核，一种亲电。以前的工作几乎完全集中在 这种酶的活性与不同的亲核底物，其中TrpB有适度的滥交。 相比之下，这里提出的研究旨在扩大酶的亲电底物范围， 制备高度官能化的α-氨基酸，以及其他类型的手性胺，如氨基醇 和β-氨基酸。这项研究的结果将是一套新的生物催化剂，可用于合成， 为新型药物化合物提供了广泛的手性胺结构单元， 提高人类疾病的诊断和治疗水平。