Issue 40, 2019

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
05 Jul 2019
Accepted
19 Aug 2019
First published
20 Aug 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 9233-9243

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

M. Artola, C. Hedberg, R. J. Rowland, L. Raich, K. Kytidou, L. Wu, A. Schaaf, M. J. Ferraz, G. A. van der Marel, J. D. C. Codée, C. Rovira, J. M. F. G. Aerts, G. J. Davies and H. S. Overkleeft, Chem. Sci., 2019, 10, 9233 DOI: 10.1039/C9SC03342D

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