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

DOI: 10.1039/C9SC03342D DOI Help

Authors: Marta Artola (Leiden University; Leiden Institute of Chemistry) , Christinne Hedberg (Leiden University) , Rhianna J. Rowland (University of York) , Lluís Raich (University of York) , Kassiani Kytidou (Leiden Institute of Chemistry) , Liang Wu (University of York) , Amanda Schaaf (Leiden University) , Maria Joao Ferraz (Leiden Institute of Chemistry) , Gijsbert A. Van Der Marel (Leiden University) , Jeroen D. C. Codée (Leiden University) , Carme Rovira (Universitat de Barcelona; Fundació Catalana de Recerca i Estudis Avancats (ICREA)) , Johannes M. F. G. Aerts (Leiden Institute of Chemistry) , Gideon J. Davies (University of York) , Herman S. Overkleeft (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 42

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 13587

Open Access Open Access

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.

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography