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 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

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 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^*

^*Corresponding author for this work

Chemistry

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 G_M1-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 - 3 Sept 2020

Bibliographical note

Keywords

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

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10.3390/molecules25174025

molecules-25-04025-v3
© 2020 by the authors.
Final published version, 7.85 MBLicence: CC BY

Cite this

Weber, P., Thonhofer, M., Averill, S., Davies, G. J., Santana, A. G., Müller, P., Nasseri, S. A., Offen, W. A., Pabst, B. M., Paschke, E., Schalli, M., Torvisco, A., Tschernutter, M., Tysoe, C., Windischhofer, W., Withers, S. G., Wolfsgruber, A., Wrodnigg, T. M., & Stütz, A. E. (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

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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",

author = "Patrick Weber and Martin Thonhofer and Summer Averill and Davies, {Gideon J.} and Santana, {Andres Gonzalez} and Philipp M{\"u}ller and Nasseri, {Seyed A.} and Offen, {Wendy A.} and Pabst, {Bettina M.} and Eduard Paschke and Michael Schalli and Ana Torvisco and Marion Tschernutter and Christina Tysoe and Werner Windischhofer and Withers, {Stephen G.} and Andreas Wolfsgruber and Wrodnigg, {Tanja M.} and St{\"u}tz, {Arnold E.}",

note = "{\textcopyright} 2020 by the authors. ",

year = "2020",

month = sep,

day = "3",

doi = "10.3390/molecules25174025",

language = "English",

volume = "25",

journal = "MOLECULES",

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Weber, P, Thonhofer, M, Averill, S, Davies, GJ, Santana, AG, Müller, P, Nasseri, SA, Offen, WA, Pabst, BM, Paschke, E, Schalli, M, Torvisco, A, Tschernutter, M, Tysoe, C, Windischhofer, W, Withers, SG, Wolfsgruber, A, Wrodnigg, TM & Stütz, AE 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

TY - JOUR

T1 - Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity

T2 - Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

AU - Weber, Patrick

AU - Thonhofer, Martin

AU - Averill, Summer

AU - Davies, Gideon J.

AU - Santana, Andres Gonzalez

AU - Müller, Philipp

AU - Nasseri, Seyed A.

AU - Offen, Wendy A.

AU - Pabst, Bettina M.

AU - Paschke, Eduard

AU - Schalli, Michael

AU - Torvisco, Ana

AU - Tschernutter, Marion

AU - Tysoe, Christina

AU - Windischhofer, Werner

AU - Withers, Stephen G.

AU - Wolfsgruber, Andreas

AU - Wrodnigg, Tanja M.

AU - Stütz, Arnold E.

PY - 2020/9/3

Y1 - 2020/9/3

N2 - 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.

AB - 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.

KW - 4-epi-isofagomine

KW - Aminocyclopentane

KW - Carbasugar

KW - G-gangliosidosis

KW - Galactosidase inhibitor

KW - Iminoalditol

KW - Pharmacological chaperone

UR - http://www.scopus.com/inward/record.url?scp=85090558251&partnerID=8YFLogxK

U2 - 10.3390/molecules25174025

DO - 10.3390/molecules25174025

M3 - Article

C2 - 32899288

AN - SCOPUS:85090558251

SN - 1420-3049

VL - 25

JO - MOLECULES

JF - MOLECULES

IS - 17

M1 - 4025

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

RS Research Professorship

Application of activity-based glycosidase probes for mechanism, enzyme discovery and clinical diagnosis

Cite this

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Projects

RS Research Professorship

Application of activity-based glycosidase probes for mechanism, enzyme discovery and clinical diagnosis

Cite this