Shusheng Wang, Omid Tavassoly, Morshed A Chowdhury, Leanne Carter, Devin Brown, Rodrigo Carasco Bravo, Anshita Madaan, Ziyang Zhang, Daniel Tesolin, Maa O Quartey, Benjamin Pluvinage, Jennifer N Nyarko, Manoj Kumar, Julia Vander Velde, Zishuo Xu, Ricardo A Feldman, Alisdair B Boraston, Darrell D Mousseau, Aarnoud C van der Spoel, Christopher P Phenix
Deficiencies in glucocerebrosidase (GCase) are associated with Parkinson's disease (PD). The mechanistic basis of this association is being intensively investigated, and new treatments are being developed aiming to boost brain GCase activity in patients. Despite the importance of GCase in PD, studies are hampered by the continued reliance on weak and non-selective inhibitors like conduritol B epoxide. Here, we report easily prepared and selective irreversible inhibitors and complementary fluorescent activity-based probes (ABPs), along with straightforward methods to inhibit and/or monitor GCase activity. Robust characterization shows that compound CAz-5c selectively inactivates GCase in vitro, in live cells, and in vivo-including GCase in the brains of live mice, at low doses, overcoming a limitation of previously reported inhibitors. Collectively, these tools can be used to generate titratable chemical models of neuropathic GCase deficiency in animals with various genetic backgrounds with unrivaled molecular precision.