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

Abstract

α-d-Gal-cyclophellitol cyclosulfamidate is a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that stabilizes α-gal A and prevents its degradation both in vitro and in cellulo by mimicry of the Michaelis complex conformation.

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

“…Recently, α-Gal-cyclosulfate 5 has been synthesized as a potential α-GalA inhibitor which mimics the initial 4 C 1 Michaelis complex [79]. Its chair conformation may render this inhibitor selective towards α-GalA (apparent IC 50 = 25 µM) and binds covalently to the enzyme adopting a 1 S 3 bound conformation [79]. Next to these covalent compounds, one of the first α-GalA inhibitors that is currently used in the clinic is the reversible inhibitor 1-deoxy-galactonojirimycin (DGJ, 6) [81] which exploits non-covalent interactions.…”

“…Epoxides are commonly used electrophilic traps and they were first used as α-galactosidase inhibitors in the form of conduritol C 2 [ 77 ]. This epoxide-based inhibitor was further developed into the synthetic form of the cyclophellitol epoxide 3 [ 78 , 79 ]. Unfortunately, epoxide 3 is not a selective α-GalA inhibitor since it also inhibits β-galactosidases GLB1 and GALC [ 79 ].…”

“…This epoxide-based inhibitor was further developed into the synthetic form of the cyclophellitol epoxide 3 [ 78 , 79 ]. Unfortunately, epoxide 3 is not a selective α-GalA inhibitor since it also inhibits β-galactosidases GLB1 and GALC [ 79 ]. In addition to the epoxides, their nitrogen-based counterpart α-galactose-configured aziridine 4 [ 78 ] has shown to be a potent inhibitor of α-GalA (apparent IC 50 = 40 nM) [ 79 ].…”

“…Unfortunately, epoxide 3 is not a selective α-GalA inhibitor since it also inhibits β-galactosidases GLB1 and GALC [ 79 ]. In addition to the epoxides, their nitrogen-based counterpart α-galactose-configured aziridine 4 [ 78 ] has shown to be a potent inhibitor of α-GalA (apparent IC 50 = 40 nM) [ 79 ]. However, similar to epoxide 3, the aziridine is not selective for α-GalA and displays a decent inhibition of GLB1 (apparent IC 50 = 0.93 µM) and GALC (apparent IC 50 = 1.1 μM).…”

“…Both epoxide- and aziridine-based inhibitors make use of the 4 C 1 4 H 3 1 S 3 conformational itineraries of retaining α-galactosidases [ 75 ], mimicking the 4 H 3 transition state which is also adopted by β-galactosidases [ 80 ]. Recently, α-Gal-cyclosulfate 5 has been synthesized as a potential α-GalA inhibitor which mimics the initial 4 C 1 Michaelis complex [ 79 ]. Its chair conformation may render this inhibitor selective towards α-GalA (apparent IC 50 = 25 μM) and binds covalently to the enzyme adopting a 1 S 3 bound conformation [ 79 ].…”