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

doi:10.3390/molecules25174025

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 journal › Article › peer-review

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 language	English
Article number	4025
Number of pages	25
Journal	Molecules
Volume	25
Issue number	17
DOIs	https://doi.org/10.3390/molecules25174025
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/molecules25174025Licence: CC BY 4.0

Cite this

Weber, P., Thonhofer, M. S., Averill, S., Davies, G. J., Gonzalez Santana, A., Müller, P., Nasseri, S. A., Offen, W. A., Pabst, B. M., Paschke, E., Schalli, M., Torvisco Gomez, A., Tschernutter, M., Tysoe, C., Windischhofer, W., Withers, S. G., Wolfsgruber, A., Wrodnigg, T. M., & Stütz, A. (2020). Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine. Molecules , 25(17), Article 4025. https://doi.org/10.3390/molecules25174025

Weber, P, Thonhofer, MS, Averill, S, Davies, GJ, Gonzalez Santana, A, Müller, P, Nasseri, SA, Offen, WA, Pabst, BM, Paschke, E, Schalli, M, Torvisco Gomez, A, Tschernutter, M, Tysoe, C, Windischhofer, W, Withers, SG, Wolfsgruber, A, Wrodnigg, TM & Stütz, A 2020, 'Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine', Molecules , vol. 25, no. 17, 4025. https://doi.org/10.3390/molecules25174025

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

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",

keywords = "4-epi-isofagomine, Aminocyclopentane, Carbasugar, G -gangliosidosis, Galactosidase inhibitor, Iminoalditol, Pharmacological chaperone",

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AU - Offen, Wendy A.

AU - Pabst, Bettina M.

AU - Paschke, Eduard

AU - Schalli, Michael

AU - Torvisco Gomez, Ana

AU - Tschernutter, Marion

AU - Tysoe, Christina

AU - Windischhofer, Werner

AU - Withers, Stephen G

AU - Wolfsgruber, Andreas

AU - Wrodnigg, Tanja Maria

AU - Stütz, Arnold

PY - 2020

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KW - G -gangliosidosis

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