Α-d-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease. Issue 40 (27th August 2019)

• Record Type: Journal Article
• Authors: Artola, Marta; Hedberg, Christinne; Rowland, Rhianna J.; Raich, Lluís; Kytidou, Kassiani; Wu, Liang; Schaaf, Amanda; Ferraz, Maria Joao; van der Marel, Gijsbert A.; Codée, Jeroen D. C.; Rovira, Carme; Aerts, Johannes M. F. G.; Davies, Gideon J.; Overkleeft, Herman S.
• Is Part Of: Chemical science. Volume 10:Issue 40(2019)
• Page Start: 9233
• Page End: 9243
• Publication Date: 2019-08-27
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9sc03342d
• Languages: English
• ISSNs: 2041-6520

Abstract

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. Abstract : 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 .