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Kok, K.; Kuo, C.L.; Katzy, R.E.; Lelieveld, L.T.; Wu, L.; Roig-Zamboni, V.; ... ; Artola Perez de Azanza, M.E. (2022)

1,6-epi-Cyclophellitol cyclosulfamidate is a bona fide lysosomal α-glucosidase stabilizer for the treatment of Pompe disease

Article / Letter to editor
α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro,Show moreα-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.Show less
All authors
Kok, K.; Kuo, C.L.; Katzy, R.E.; Lelieveld, L.T.; Wu, L.; Roig-Zamboni, V.; Marel, G.A. van der; Codee, J.D.C.; Sulzenbacher, G.; Davies, G.J.; Overkleeft, H.S.; Aerts, J.M.F.G.; Artola Perez de Azanza, M.E.
Date
2022-08-02
Journal
Journal of the American Chemical Society
Volume
144
Issue
32
Pages
14819 - 14827
DOI
doi:10.1021/jacs.2c05666
Link
https://pubs.acs.org/doi/10.1021/jacs.2c05666

Funding

Sponsorship
NWO
Grant number
NWO-CW, ChemThem