Covalent Cyclitol Aziridines Deliver a Brain-Penetrant, Selective GBA2 Inhibitor
- GBA2 has lacked inhibitors that separate it from GBA1 and glucosylceramide synthase; the team built a focused library of electrophilic cyclitols (epoxides, cyclic sulfates, N-alkyl aziridines) from earlier β-D-arabinofuranose activity-based probes.
- Profiling against GBA1, GBA2, GBA3 and glucosylceramide synthase identified covalent inhibitors selective for GBA2.
- The lead is reported as the first brain-penetrant covalent inhibitor to selectively inactivate GBA2 in vivo.
💡 Points
Turning an activity-based-probe scaffold into an in vivo tool compound is a neat path, and selectivity over GBA1 and GCS is precisely what GBA2 biology has been missing. For anyone working on sphingolipid or lysosomal storage disorders this is a usable tool. My open question is the covalent off-target profile at in vivo exposure, since aziridines are not quiet electrophiles.