Mechanistic insights into the chaperoning of human lysosomal-galactosidase activity: highly functionalized aminocyclopentanes and C-5a-substituted derivatives of 4-epi-isofagomine

DOI: 10.3390/molecules25174025

Authors: Patrick Weber (Graz University of Technology) , Martin Thonhofer (Graz University of Technology) , Summer Averill (Graz University of Technology) , Gideon J. Davies (University of York) , Andres Gonzalez Santana (University of British Columbia) , Philipp Müller (Graz University of Technology) , Seyed A. Nasseri (University of British Columbia) , Wendy A. Offen (University of York) , Bettina M. Pabst (MedUni Graz) , Eduard Paschke (MedUni Graz) , Michael Schalli (Graz University of Technology) , Ana Torvisco (Graz University of Technology) , Marion Tschernutter (MedUni Graz) , Christina Tysoe (University of British Columbia) , Werner Windischhofer (MedUni Graz) , Stephen G. Withers (University of British Columbia) , Andreas Wolfsgruber (Graz University of Technology) , Tanja M. Wrodnigg (Graz University of Technology) , Arnold E. Stütz (Graz University of Technology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecules , VOL 25

State: Published (Approved)
Published: September 2020

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.

Journal Keywords: iminoalditol; 4-epi-isofagomine; carbasugar; aminocyclopentane; galactosidase inhibitor; pharmacological chaperone; GM1-gangliosidosis

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography