Unlocking New Chemistries in Extant Enzymes for Synthesizing Bioactive Molecules

解锁现有酶中用于合成生物活性分子的新化学成分

• 批准号: 10784165
• 负责人: Edwin Alfonzo
• 金额: $ 11.6万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784165
• 关键词: Adoption; Amination; Amines; Biochemical; Biological Availability; Biology; Brain; Chemical Industry; Chemicals; Chemistry; Clinical Medicine; Complex; Dimethyl Sulfoxide; Directed Molecular Evolution; Drug Industry; Electrons; Engineering; Enzymes; Exclusion; Exhibits; Grant; Health; Heme; Hemeproteins; Human; Knowledge; Laboratories; Ligands; Medicine; Mentors; Metals; Methods; Molecular; Molecular Structure; Nitrogen; Organic solvent product; Organism; Outcome; Oxidants; Oxidases; Penetrance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevalence; Price; Process; Property; Reaction; Side; Source; Sulfoxide; Sulfur; Technology; Time; Toxic effect; Transferase; catalyst; chemical reaction; clinical candidate; cost; drug discovery; enzyme activity; enzyme mechanism; experience; functional group; improved; innovation; methionine sulfoxide reductase; nitrene; oxidation; pharmacokinetics and pharmacodynamics; prospective; reaction rate; success; therapeutic candidate; thioether

Project Summary/Abstract: Enzymes, supported by their macromolecular structure, can catalyze chemical transformations with exquisite control, delivering products with high selectivity. The mechanisms that enzymes can support, however, are limited, making chemical technologies often the preferred method for synthesis, regardless of cost, toxicity, and environmental burden. Herein are two proposals to expand the activity of enzymes beyond their natural function for synthesizing medicinally important functional groups. Specifically, heme enzymes and methionine sulfoxide reductases are tasked for the first time with performing aminations and oxidations, respectively, toward synthesizing chiral trifluoroethylamines, sulfoxides, and sulfoximines, motifs known to bestow function and drug- like properties to therapeutics and clinical candidates. By engineering enzymes to catalyze reactions beyond their natural capabilities, we are boldly pushing the boundaries of biology and chemistry. This innovation has the potential to revolutionize the way we make molecules and introduce new chemical reactions that can be performed in living organisms. Furthermore, these efforts will unlock activities never before seen in biocatalysis, expanding the repertoire of genetically encoded chemical transformations. The success of this proposal will afford high-value molecules and biorenewable catalysts that may lead to the discovery of new medicines and strategies to regulate biology, with the ultimate objective of informing and improving human health.

项目概要/摘要： 酶在其大分子结构的支持下，可以催化化学转化， 控制，提供高选择性的产品。然而，酶可以支持的机制是 有限的，使化学技术往往是首选的合成方法，无论成本，毒性， 环境负担。这里有两个建议，以扩大酶的活动超出其自然功能 用于合成医学上重要的功能基团。特别是血红素酶和蛋氨酸亚砜 还原酶的任务是第一次执行胺化和氧化，分别向 合成手性三氟乙胺、亚砜和亚砜亚胺，已知这些基序赋予功能和药物- 类似于治疗学和临床候选物的性质。通过改造酶来催化反应， 他们的自然能力，我们正在大胆地推动生物学和化学的界限。这项创新具有 有可能彻底改变我们制造分子的方式，并引入新的化学反应， 在生物体中进行。此外，这些努力将开启生物催化中从未见过的活动， 扩大了基因编码的化学转化的所有功能。这项提案的成功将 提供高价值的分子和生物可再生催化剂，可能导致发现新的药物， 生物监管战略，最终目标是宣传和改善人类健康。