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Pang, Zhengyuan; Schafroth, Michael A.; Ogasawara, Daisuke; Wang, Yu; Nudell, Victoria; Lal, Neeraj K.; Yang, Dong; Wang, Kristina; Herbst, Dylan M.; Ha, Jacquelyn; Guijas, Carlos; Blankman, Jacqueline L.; Cravatt, Benjamin F.; Ye, Li
Cell, 05/2022, Volume: 185, Issue: 10Journal Article
The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose-dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue. Display omitted •Tissue clearing greatly improves click chemistry labeling in mammalian tissues•CATCH enables brain-wide, subcellular in situ imaging of drug-target engagement•CATCH allows cellular drug-target identification and validation•CATCH quantitively determines on- and off-target in vivo drug binding Clearing-assisted tissue click chemistry (CATCH) allows for the in vivo visualization of target-bound drug molecules and enables the identification of drug distribution and engagement in mammalian tissue.
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