Discovery of Selective\nInhibitors for the Lysosomal\nParkinson’s Disease Channel TMEM175

TMEM175 is a lysosomal potassium and proton channel that\nis associated\nwith the development of Parkinson’s disease. Advances in understanding\nthe physiological roles of TMEM175 have been hampered by the absence\nof selective inhibitors, and studies involving genetic perturbations\nhave yielded conflicting results. Here, we report the discovery and\ncharacterization of the first reported TMEM175-selective inhibitors,\n2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of\nhuman TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore\nblockers, binding at distinct sites in the pore and occluding the\nion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6\nincreases the level of lysosomal macromolecule catabolism, thereby\naccelerating macropinocytosis and other digestive processes. These\ninhibitors may serve as valuable tools to study the roles of TMEM175\nin regulating lysosomal function and provide useful templates for\nfuture therapeutic development in Parkinson’s disease.