β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors.
7 affiliations
- 1Departments of Medical Biochemistry and Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University , P.O. Box 9502, 2300RA Leiden, The Netherlands.
- 2Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franquès 1, 08028Barcelona, Spain.
- 3Department of Chemistry, York Structural Biology Laboratory, University of York, Heslington, YorkYO10 5DD, U.K.
- 4Department of Medical Biochemistry, Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam1105AZ, The Netherlands.
- 5Amsterdam Gastroenterology, Endocrinology, and Metabolism Institute, Amsterdam University Medical Center, Amsterdam1105AZ, The Netherlands.
- 6Amsterdam Cardiovascular Sciences Institute, Amsterdam University Medical Center, Amsterdam1105AZ, The Netherlands.
- 7Fundació Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010Barcelona, Spain.
Abstract
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.
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BibTeX
@article{lammers2026βdarabinofuranoseconfigured,
title = {{β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors.}},
author = {Rob F Lammers and Qin Su and Laura Mazo and Wendy A Offen and Roelof Ottenhoff and Mats J Bulterman and Martijn van der Lienden and Maria J Ferraz and Florian Küllmer and Zahid Ilhan and Hans van den Elst and Ingeborg van der Made and Cindy P A A van Roomen and Anne de Jongh and Adrianus M C H van den Nieuwendijk and Rolf G Boot and Noam Zelcer and Gideon J Davies and Carme Rovira and Herman S Overkleeft and Johannes M F G Aerts and Marta Artola},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c09754},
url = {https://europepmc.org/article/MED/42913544},
note = {CC BY},
}
RIS
TY - JOUR
TI - β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors.
AU - Rob F Lammers
AU - Qin Su
AU - Laura Mazo
AU - Wendy A Offen
AU - Roelof Ottenhoff
AU - Mats J Bulterman
AU - Martijn van der Lienden
AU - Maria J Ferraz
AU - Florian Küllmer
AU - Zahid Ilhan
AU - Hans van den Elst
AU - Ingeborg van der Made
AU - Cindy P A A van Roomen
AU - Anne de Jongh
AU - Adrianus M C H van den Nieuwendijk
AU - Rolf G Boot
AU - Noam Zelcer
AU - Gideon J Davies
AU - Carme Rovira
AU - Herman S Overkleeft
AU - Johannes M F G Aerts
AU - Marta Artola
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c09754
UR - https://europepmc.org/article/MED/42913544
AB - 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.
SN - 0002-7863
SN - 1520-5126
ER -