Toolkit for Fast, Multipurpose and Inducible Bioorthogonal Chemistry

快速、多用途和诱导生物正交化学工具包

基本信息

批准号：
9899272
负责人：
JOSEPH M FOX
金额：
$ 35.88万
依托单位：
UNIVERSITY OF DELAWARE
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：
2019-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899272
关键词：
3-Dimensional Acute Affinity Binding Biological Response Modifier Therapy Biology Biotechnology Blood Circulation CC49 antibody Cell surface Cells Chelating Agents Chemicals Chemistry Colon Carcinoma Coupling Development Disease Drug Delivery Systems Drug Kinetics Environment Enzymes Generations Goals Heating In Situ Label Ligands Ligation Light Locales Mediating Methodology Methods Modeling N-terminal Permeability Pharmaceutical Preparations Plant Resins Procedures Prodrugs Property Protein Engineering Proteins Proteomics Radiochemistry Reaction Reagent Reporter Role Safety Side Site Solubility Surface System Techniques Technology Time Tissues Visible Radiation Work antibody conjugate base cancer cell catalyst cytotoxic design drug candidate fluorophore functional group improved interest materials science new technology protein purification receptor small molecule tissue culture tool trafficking

项目摘要

Project Summary The goal of this proposal will be to develop a diverse set of new chemical tools centered on tetrazine ligation– the fastest known bioorthogonal reaction. This proposal describes new tools for the safe synthesis and direct coupling of `minimalist' tetrazines to any molecule of interest, including API's and fluorescent reporters. We also propose to develop specialized tetrazines that can serve a dual role in enabling protein purification followed by subsequent site-selective bioorthogonal chemistry. Finally, we propose to develop efficient catalytic methods for `turning on' rapid bioorthogonal chemistry in cellular context. We will develop tool molecules with high stability in the cellular environment in their `off' state, and the fastest bioorthogonal reactions to date in their `on' state. An application of the catalytically inducible tetrazine ligation is new method of drug release where a photocatalyst-antibody conjugate is pretargeted to a disease site, and red light is used to drive the local release of a cytotoxic reagent from a photocaged prodrug.

项目概要该提案的目标是开发一套以关于四嗪连接——已知最快的生物正交反应该提案描述了。用于安全合成“极简”四嗪并将其直接偶联到任何物质的新工具感兴趣的分子，包括 API 和荧光生产者。开发可在蛋白质纯化中发挥双重作用的专用四嗪最后，我们建议进行后续的位点选择性生物正交化学。开发有效的催化方法来“开启”快速生物正交化学我们将开发在细胞中具有高稳定性的工具分子。环境处于“关闭”状态，而迄今为止最快的生物正交反应处于“开启”状态催化诱导四嗪连接的一种应用是新方法。光催化剂-抗体缀合物预先靶向疾病部位的药物释放，红光用于驱动细胞毒性试剂从光笼中局部释放前药。