Development of Bifunctional and Light Activated ReACT Bioconjugation Reagents via Nitrone Photoisomerization

通过硝酮光异构化开发双功能光激活 ReACT 生物共轭试剂

• 批准号: 10389513
• 负责人: Kacper Skakuj
• 金额: $ 6.72万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389513
• 关键词: Antibodies; Biocompatible Materials; Biological; Chemical Structure; Chemicals; Chemistry; Clinical; Cross-Linking Reagents; Development; ERBB2 gene; Immunotherapy; In Situ; Label; Laboratories; Libraries; Ligation; Light; Methionine; Methodology; Methods; Organic Synthesis; Oxidation-Reduction; Photochemistry; Post-Translational Protein Processing; Proteins; Reaction; Reagent; Regression Analysis; Research; Research Personnel; Route; Sampling; Structure; Sulfur; Time; Training; absorption; chemical stability; crosslink; experience; functional group; method development; nitrone; novel; oxaziridine; oxidation; skills; spatiotemporal; tool

PROJECT SUMMARY/ABSTRACT The unique reactivity of oxaziridines towards methionine sidechains via N-transfer has been successfully leveraged to make powerful bioconjugation reagents used by numerous research groups. However, the utility of this reagent is limited by the difficulty of incorporating secondary reactive handles and a narrow cargo scope due to the harsh synthesis conditions and sensitivity of oxaziridines. Photoisomerization of nitrones provides a mild method of oxaziridine synthesis. This route to oxaziridines allows for incorporation of cargo not accessible with current synthetic methods and presents a powerful way of controlling oxaziridine reactivity using light. This proposal aims to elucidate quantitative relationships between nitrone chemical structure and its ability to isomerize to oxaziridines and the resulting oxaziridine bioconjugation reactivity. Nitrone photoisomerization will be leveraged to synthesize bivalent reagents that incorporate other commonly used click handles. Finally, the exquisite control over oxaziridine reactivity provided by the photoisomerization will be used to uncage oxaziridine reactivity in situ for protein modifications. These studies will greatly expand the utility of this valuable class of bioconjugation reagents.

项目概要/摘要 氧氮丙啶通过 N-转移对甲硫氨酸侧链的独特反应性已被证实 成功地用来制造强大的生物共轭试剂，被众多研究小组使用。 然而，该试剂的实用性因难以掺入次级反应性而受到限制。 由于氧氮丙啶的合成条件苛刻和敏感性，手柄和货物范围狭窄。 硝酮的光异构化提供了一种温和的氧氮丙啶合成方法。这条路线到 氧氮丙啶允许掺入目前合成方法无法获得的货物，并且 提出了一种利用光控制氧氮丙啶反应性的有效方法。该提案旨在阐明 硝酮化学结构与其异构化能力之间的定量关系 氧氮丙啶和由此产生的氧氮丙啶生物共轭反应性。硝酮光致异构化 用于合成包含其他常用点击手柄的二价试剂。最后， 光异构化提供的对氧杂氮丙啶反应性的精确控制将用于 原位释放氧氮丙啶反应性以进行蛋白质修饰。这些研究将极大地拓展 这类有价值的生物共轭试剂的实用性。