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oai:figshare.com:article/34021988 2026-09-29T08:03:32Z category_4 category_12 category_13 category_14 category_15 category_16 category_19 category_873 category_46 category_734 category_64 category_128 portal_63 item_type_6 month_year_09_2026

β‑d‑Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors Rob F. Lammers (25136006) Qin Su (31034) Laura Mazo (19687603) Wendy A. Offen (25136009) Roelof Ottenhoff (128566) Mats J. Bulterman (25136012) Martijn van der Lienden (23601877) Maria J. Ferraz (1761286) Florian Küllmer (8810810) Zahid Ilhan (25136015) Hans van den Elst (2062972) Ingeborg van der Made (166576) Cindy P. A. A. van Roomen (12067973) Anne de Jongh (25136018) Adrianus M. C. H. van den Nieuwendijk (24545017) Rolf G. Boot (783479) Noam Zelcer (3775795) Gideon J. Davies (367307) Carme Rovira (1275285) Herman S. Overkleeft (128584) Johannes M. F. G. Aerts (4006295) Marta Artola (1632661) Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Physiology Pharmacology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer Hematology >- alkyl aziridines selectively label gba2 selectively inhibited gba2 selectively inactivates gba2 nanomolar gba2 inhibitors dissect gba2 biology covalent gba2 inhibition robust cellular activity detectable gcs inhibition results establish β configured cyclitol aziridines 5 </ b cyclitol aziridine covalent inhibitor vivo </ n </ araf </ well suited versatile inhibitor sphingolipid metabolism murine plasma lysosomal glucosylceramidase living cells inhibitory activity including epoxides hindered efforts high selectivity glucosylceramide synthase glucosidase involved gcs revealed focused library diverse set cyclic sulfates biochemical evaluation bearing cyclitols alkyne aziridine >, particularly Neutral glucosylceramidase GBA2 is a retaining β-d-glucosidase involved in sphingolipid metabolism and implicated in neurological lysosomal storage disorders, yet the lack of highly selective chemical inhibitors has hindered efforts to disentangle its function from that of glucosylceramide synthase (GCS) and lysosomal glucosylceramidase (GBA1). Here, we report the development of the first brain-penetrant, covalent inhibitor that selectively inactivates GBA2 in vivo. Building on β-d-arabinofuranose-configured (β-d-Araf) cyclitol aziridine activity-based probes previously shown to covalently and selectively label GBA2, we designed and synthesized a focused library of electrophile-bearing cyclitols, including epoxides, cyclic sulfates, and a diverse set of N-alkyl aziridines. Biochemical evaluation of their inhibitory activity against GBA1, GBA2, GBA3 and GCS revealed that several N-alkyl aziridines are highly selective, nanomolar GBA2 inhibitors. Lead compounds also demonstrated metabolic stability in murine plasma, robust cellular activity and high selectivity in living cells, with no detectable GCS inhibition. Notably, octyl-alkyne aziridine 5 selectively inhibited GBA2 in mouse brain, representing the first covalent GBA2 inhibitor with demonstrated in vivo activity and brain permeability. Together, these results establish β-d-Araf cyclitol aziridine 5 as a versatile inhibitor for selective, covalent GBA2 inhibition, well suited to dissect GBA2 biology in vivo, particularly in neurological lysosomal storage disorders. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/jacs.6c09754.s001 https://figshare.com/articles/journal_contribution/_d_Arabinofuranose-configured_Cyclitol_Aziridines_as_Selective_Brain-penetrant_Covalent_GBA2_Inhibitors/34021988 CC BY-NC 4.0