Rational design of glycosidase pharmacological chaperones: from covalent cyclic sulfates to reversible cyclic sulfamidates

S7.1 Synthetic glycomimetic glycosidase inhibitors
Location (hall): 
Start/end time: 
Wednesday, July 3, 2019 - 12:15 to 12:30

Marta Artola1, Christinne Hedberg1, Rhianna Rowland2, Kassiani Kytidou1, Lluís Raich3, Liang Wu3, Maria J.  Ferraz1, Jeroen D. Codée1, Gijsbert A. van der Marel1, Carme Rovira3, Johannes M. F. G.  Aerts1, Gideon J.  Davies2, Herman S. Overkleeft1

1Biochemistry and Bio-organic Synthesis Department, Leiden University, Leiden, The Netherlands, 2Department of Chemistry, University of York, York, United Kingdom, 3Departament de Química Inorgànica i Orgànica, Universitat de Barcelona, Barcelona, Spain

“Cyclosulfates”, carbohydrate analogues bearing a cyclic sulfate as an electrophilic trap, have recently been described as a conceptually new class of glycosidase inhibitors. α-Glu-cyclosulftate adopts a 4C1 conformation and covalently inhibits α-glucosidases in a potent and selective manner by mimicking the Michaelis conformation.[1] Modifying the cyclophellitol core to galactose configuration has resulted in the generation of α-Gal A irreversible inhibitors (Figure 1A). Exploration of diverse bioisosteres and reducing the electrophilicity of the cyclic sulfate has afforded a novel competitive α-gal A inhibitor that acts as a chaperone for Fabry Disease (Figure 1B). Herein, we present a novel class of reversible glycosidase inhibitors, which we have validated by metadynamics simulations, 3-D crystal structure analysis in complex with recombinant human α-galactosidase (Fabrazyme), activity-based protein profile[2] as well as in vitro and in situ cell experiments. Remarkably, α-gal-cyclosulfamidate behaves as a pharmacological chaperone for Fabry disease: α-Gal A activity is increased when cells are treated with recombinant enzyme supplemented with α-Gal-cyclosulfamidate and toxic metabolite levels (Gb3 and LysoGb3) are corrected in classical mutant R301X Fabry cell lines. Variation of the cyclosulfamidate configuration provides diverse glycosidase pharmacological chaperones.

Figure 1. From covalent α-Gal-cyclosulfate to competitive α-Gal-cyclosulfamidate. A. Crystal structures of human α-Gal A bound to α-Gal-cyclosulfate and α-Gal-cyclosulfamidate in a covalent and reversible manner respectively. B. Chaperone effect: α-Gal A activity is increased when cells are treated with ERT supplemented with α-Gal-cyclosulfamidate and toxic LysoGb3 levels are corrected.

  1. M. Artola, C. Rovira, G. J. Davies, H. S. Overkleeft. ACS Cent. Sci. 2017, 3, 784−793.
  2. L. I. Willems, J. M. F. G. Aerts, H. S. Overkleeft. J. Am. Chem. Soc., 2014, 136, 11622−11625.