“Cyclosulfates”, carbohydrate analogues bearing a cyclic sulfate as an electrophilic trap, have recently been described as a conceptually new class of glycosidase inhibitors. α-Glu-cyclosulftate adopts a 4C1 conformation and covalently inhibits α-glucosidases in a potent and selective manner by mimicking the Michaelis conformation. Modifying the cyclophellitol core to galactose configuration has resulted in the generation of α-Gal A irreversible inhibitors (Figure 1A). Exploration of diverse bioisosteres and reducing the electrophilicity of the cyclic sulfate has afforded a novel competitive α-gal A inhibitor that acts as a chaperone for Fabry Disease (Figure 1B). Herein, we present a novel class of reversible glycosidase inhibitors, which we have validated by metadynamics simulations, 3-D crystal structure analysis in complex with recombinant human α-galactosidase (Fabrazyme), activity-based protein profile as well as in vitro and in situ cell experiments. Remarkably, α-gal-cyclosulfamidate behaves as a pharmacological chaperone for Fabry disease: α-Gal A activity is increased when cells are treated with recombinant enzyme supplemented with α-Gal-cyclosulfamidate and toxic metabolite levels (Gb3 and LysoGb3) are corrected in classical mutant R301X Fabry cell lines. Variation of the cyclosulfamidate configuration provides diverse glycosidase pharmacological chaperones.
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