Selective Protein Degradation through Tetrazine Ligation of Genetically Incorporated Unnatural Amino Acids.

Small molecule-responsive tags for targeted protein degradation are valuable tools for fundamental research and drug target validation. Here, we show that genetically incorporated unnatural amino acids bearing a strained alkene or alkyne functionality can act as a minimalist tag for targeted protein degradation. Specifically, we observed the degradation of strained alkene- or alkyne-containing kinases and E2 ubiquitin-conjugating enzymes upon treatment with hydrophobic tetrazine conjugates.