α- d -Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α- d -galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with a recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy, a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α- d -gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally constrained competitive glycosidase inhibitors that act by mimicry of the Michaelis complex conformation. We found that d -galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α- d -galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo .