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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：在其大分子结构支持的酶中，可以用精致的化学转化催化化学转化控制，以高选择性提供产品。但是，酶可以支持的机制是有限，使化学技术通常是合成的首选方法，无论成本，毒性和毒性如何环境负担。这是两个提议，以扩大酶的活性超出其自然功能用于综合具有药物重要的官能团。具体而言，血红素酶和甲硫氨酸亚氧化酶还要首次将还原酶进行执行氨和氧化的任务合成的手性三氟乙胺，亚氧化胺和亚磺氧胺，已知的基序赋予功能和药物 - 就像治疗和临床候选物的特性一样。通过工程酶催化反应它们的自然能力，我们大胆地突破了生物学和化学的界限。这项创新有有可能改变我们制造分子并引入新的化学反应的潜力在生物体中表演。此外，这些努力将解锁生物催化中从未见过的活动，扩大了遗传编码的化学转化的曲目。该提议的成功将提供高价值分子和可生物可生产催化剂，可能导致发现新药物和调节生物学的策略，以告知和改善人类健康的最终目标。