Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

Patrick Weber, Martin Simon 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 Gomez, Marion Tschernutter, Christina Tysoe, Werner Windischhofer, Stephen G Withers, Andreas Wolfsgruber, Tanja Maria Wrodnigg, Arnold Stütz*

*Corresponding author for this work

Research output: Contribution to journalArticle

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
Original languageEnglish
Article number4025
Number of pages25
JournalMolecules
Volume25
Issue number17
DOIs
Publication statusPublished - 2020

Keywords

  • 4-epi-isofagomine
  • Aminocyclopentane
  • Carbasugar
  • G -gangliosidosis
  • Galactosidase inhibitor
  • Iminoalditol
  • Pharmacological chaperone

ASJC Scopus subject areas

  • Drug Discovery
  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Physical and Theoretical Chemistry
  • Pharmaceutical Science
  • Organic Chemistry

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