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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