Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine
Patrick Weber,
Martin Thonhofer,
Summer Averill,
Gideon J. Davies,
Andres Gonzalez Santana,
Philipp Müller,
Seyed A. Nasseri,
Wendy A. Offen,
Bettina M. Pabst,
Eduard Paschke,
Michael Schalli,
Ana Torvisco,
Marion Tschernutter,
Christina Tysoe,
Werner Windischhofer,
Stephen G. Withers,
Andreas Wolfsgruber,
Tanja M. Wrodnigg,
Arnold E. Stütz
Affiliations
Patrick Weber
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Martin Thonhofer
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Summer Averill
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Gideon J. Davies
Department of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UK
Andres Gonzalez Santana
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Philipp Müller
Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Seyed A. Nasseri
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Wendy A. Offen
Department of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UK
Bettina M. Pabst
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
Eduard Paschke
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
Michael Schalli
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Ana Torvisco
Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Marion Tschernutter
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
Christina Tysoe
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Werner Windischhofer
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
Stephen G. Withers
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Andreas Wolfsgruber
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Tanja M. Wrodnigg
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
Arnold E. Stütz
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
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.
