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

Lookup NU author(s): Rhianna RowlandORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

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.

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Author(s): Artola M, Hedberg C, Rowland RJ, Raich L, Kytidou K, Wu L, Schaaf A, Ferraz MJ, van der Marel GA, Codee JDC, Rovira C, Aerts JMFG, Davies GJ, Overkleeft HS

Publication type: Article

Publication status: Published

Journal: Chemical Science

Year: 2019

Volume: 10

Pages: 9233-9243

Online publication date: 20/08/2019

Acceptance date: 19/08/2019

Date deposited: 22/12/2021

ISSN (print): 2041-6520

ISSN (electronic): 2041-6539

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/C9SC03342D

DOI: 10.1039/C9SC03342D

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