1,6- epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal α-Glucosidase Stabilizer for the Treatment of Pompe Disease

Abstract

α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.

Metadata

Authors/Creators:

Kok, Ken
Kuo, Chi Lin
Katzy, Rebecca E.
Lelieveld, Lindsey T.
Wu, Liang https://orcid.org/0000-0003-0294-7065
Roig-Zamboni, Véronique
Van Der Marel, Gijsbert A.
Codée, Jeroen D.C.
Sulzenbacher, Gerlind
Davies, Gideon J. https://orcid.org/0000-0002-7343-776X
Overkleeft, Herman S.
Aerts, Johannes M.F.G.
Artola, Marta

Funding Information: We thank The Netherlands Organization for Scientific Research (NWO-CW, ChemThem grant to J.M.F.G.A. and H.S.O.), the European Research Council (ERC-2011-AdG-290836 “Chembiosphing” to H.S.O., ERC-2012-AdG-322942 “Glycopoise” to G.J.D. and ERC-2020-SyG-951231 “Carbocentre” to H.S.O. and G.J.D.), Sanofi Genzyme (research grant to J.M.F.G.A. and H.S.O. for financial support, postdoctoral contract to M.A. and Myozyme supply). G.J.D. is supported by the Royal Society though the Ken Murray Research Professorship. We kindly thank Giancarlo Parenti, Federico II University Naples, for providing Myozyme samples for structural studies. We thank Andrea Dardis and the Biobank from Patients Affected by ALS Neuromuscular and Lysosomal Diseases (University Hospital of Udine, Italy) for providing us with plasma samples from Pompe patients. We thank Synchrotron Soleil for beam time allocation and the beam line staff for assistance with data collection. This work was also supported in part by the CNRS and the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01. Funding Information: We thank The Netherlands Organization for Scientific Research (NWO-CW, ChemThem grant to J.M.F.G.A. and H.S.O.), the European Research Council (ERC-2011-AdG-290836 “Chembiosphing” to H.S.O., ERC-2012-AdG-322942 “Glycopoise” to G.J.D., and ERC-2020-SyG-951231 “Carbocentre” to H.S.O. and G.J.D.), Sanofi Genzyme (research grant to J.M.F.G.A. and H.S.O. for financial support, postdoctoral contract to M.A. and Myozyme supply). G.J.D. is supported by the Royal Society though the Ken Murray Research Professorship. We kindly thank Giancarlo Parenti, Federico II University, Naples, for providing Myozyme samples for structural studies. We thank Andrea Dardis and the Biobank from Patients Affected by ALS, Neuromuscular and Lysosomal Diseases (University Hospital of Udine, Italy) for providing us with plasma samples from Pompe patients. We thank Synchrotron Soleil for beam time allocation and the beam line staff for assistance with data collection. This work was also supported in part by the CNRS and the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01. Publisher Copyright: © 2022 The Authors. Published by American Chemical Society.

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