Reactivity-Based Chemical Tools for Biomedical Research

Selective reactions with proteins carrying unique chemical reporters in living cells offer a powerful tool to study protein dynamics in their native environment. In this talk, I will discuss our work on the development of tetrazole and strained alkene reagents that allow rapid and site-specific protein labeling both in vitro and in living cells. Our optimization efforts have resulted in the tetrazole reagents with tunable photoactivation wavelength, including two-photon laser light, as well as the genetically encoded alkene reporters with robust reaction kinetics. In addition, the discovery of unexpected high reactivity of spiroalkene in tetrazine ligation as well as its application in biophysical studies of class B GPCRs will be presented. I will conclude the talk by discussing our recent efforts in exploiting photo-cross-linking reactivity of tetrazoles for identifying drug targets/off-targets in situ as well as mapping intracellular protein-protein interactions.