Toolkit for Fast, Multipurpose and Inducible Bioorthogonal Chemistry

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，而迄今为止最快的生物正交反应处于“打开”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

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.