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

• 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
• 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

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.

项目摘要 该提案的目标是开发一套多样化的新化学工具， 四嗪连接-已知最快的生物正交反应。该提案描述了 安全合成和直接偶联“最低限度”四嗪到任何 目标分子，包括API和荧光报告分子。我们亦建议 开发专门的四嗪，可以在蛋白质纯化中发挥双重作用 随后进行位点选择性生物正交化学。最后，我们建议 开发有效的催化方法，“开启”快速生物正交化学， 细胞背景我们将开发在细胞内具有高稳定性的工具分子， 环境处于“关闭”状态，迄今为止最快的生物正交反应处于“开启”状态 状态催化诱导四嗪连接的应用是一种新的方法， 在光催化剂-抗体偶联物预先靶向疾病部位的情况下的药物释放， 红光用于驱动细胞毒性试剂从光笼中局部释放 前药