A fluorogenic-inhibitor-based probe for profiling and imaging of monoamine oxidase A in live human glioma cells and clinical tissues

Monoamine oxidase A (MAO-A) plays a critical role in the development of glioma and other neurological disorders. Specific analysis of MAO-A activities and its drug interactions in intact tissue is important for biological and pharmacological research, but highly challenging with current chemical tools. Fluorogenic-inhibitor-based probes offer improved selectivity, sensitivity, and effectiveness to image and profile endogenous targets in an activity-based manner from mammalian cells, which are however rare. Herein, we report HD1 as the first fluorogenic-inhibitor-based probe that can selectively label endogenous MAO-A from various mammalian cells and clinical tissues. The probe was delicately designed based on N-propargyl tetrahydropyridine, a small MAO-A-specific fluorogenic and inhibitory war-head, so that the probe becomes fluorescent upon in situ enzymatic oxidation and covalent labeling of MAO-A. With the excellent binding affinity (vin itro K_i = 285 nM) and fluorogenic properties, HD1 offers a promising approach to simultaneously image endogenous MAO-A activities by super-resolution fluorescence microscopy and study its drug interactions by subsequent activity-based protein profiling, in both live cells and human glioma tissues. [Figure not available: see fulltext.]