UBC Faculty Research and Publications

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine Weber, Patrick; Thonhofer, Martin; Averill, Summer; Davies, Gideon J.; Santana, Andres Gonzalez; Müller, Philipp; Nasseri, Seyed A.; Offen, Wendy A.; Pabst, Bettina M.; Paschke, Eduard; Schalli, Michael; Torvisco, Ana; Tschernutter, Marion; Tysoe, Christina; Windischhofer, Werner; Withers, Stephen G.; Wolfsgruber, Andreas; Wrodnigg, Tanja M.; Stütz, Arnold E.

Abstract

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

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