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.
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. The work will advance new biotechnological and biomedical applications, new chemical tools for labeling biomolecules in the intracellular environment, and new technology for drug delivery that will enhance our ability to selectively kill disease tissue without harming healthy tissue.
