Rational design of cell active C2-modified DGJ analogues for the inhibition of human α-galactosidase A (GALA)

Roger A. Ashmus; Yang Wang; Manuel González-Cuesta; Dustin T. King; Ben Tiet; Pierre-André Gilormini; José M. García Fernández; Carmen Ortiz Mellet; Robert Britton; David J. Vocadlo

doi:10.1039/D1OB01526E

Rational design of cell active C2-modified DGJ analogues for the inhibition of human α-galactosidase A (GALA)†

Roger A. Ashmus,

‡^a Yang Wang,‡§^a Manuel González-Cuesta,^b Dustin T. King,^c Ben Tiet,^a Pierre-André Gilormini,

^a José M. García Fernández,

^d Carmen Ortiz Mellet,

^b Robert Britton

*^a and David J. Vocadlo

*^ac

Author affiliations

* Corresponding authors

^a Department of Chemistry and Simon Fraser University, British Columbia, Burnaby, Canada
E-mail: dvocadlo@sfu.ca, robert_britton@sfu.ca

^b Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain

^c Department of Molecular Biology and Biochemistry Simon Fraser University, British Columbia, Burnaby, Canada

^d Instituto de Investigaciones Químicas (IIQ), CSIC-Universidad de Sevilla, Sevilla 41092, Spain

Abstract

We report the rational design and synthesis of C2-modified DGJ analogues to improve the selective inhibition of human GALA over other glycosidases. We prepare these analogues using a concise route from non-carbohydrate materials and demonstrate the most selective inhibitor 7c (∼100-fold) can act in Fabry patient cells to drive reductions in levels of the disease-relevant glycolipid Gb3.

This article is part of the themed collection: Chemical Biology in OBC

Organic & Biomolecular Chemistry

Rational design of cell active C2-modified DGJ analogues for the inhibition of human α-galactosidase A (GALA)†

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Rational design of cell active C2-modified DGJ analogues for the inhibition of human α-galactosidase A (GALA)

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