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Issue 40, 2019
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α-d-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

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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

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Publication details

The article was received on 05 Jul 2019, accepted on 19 Aug 2019 and first published on 20 Aug 2019


Article type: Edge Article
DOI: 10.1039/C9SC03342D
Chem. Sci., 2019,10, 9233-9243
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    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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