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Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*.

Authors :
Zhu S
Jagadeesh Y
Tran AT
Imaeda S
Boraston A
Alonzi DS
Poveda A
Zhang Y
Désiré J
Charollais-Thoenig J
Demotz S
Kato A
Butters TD
Jiménez-Barbero J
Sollogoub M
Blériot Y
Source :
Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2021 Aug 05; Vol. 27 (44), pp. 11291-11297. Date of Electronic Publication: 2021 Jul 02.
Publication Year :
2021

Abstract

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.<br /> (© 2021 Wiley-VCH GmbH.)

Details

Language :
English
ISSN :
1521-3765
Volume :
27
Issue :
44
Database :
MEDLINE
Journal :
Chemistry (Weinheim an der Bergstrasse, Germany)
Publication Type :
Academic Journal
Accession number :
34106504
Full Text :
https://doi.org/10.1002/chem.202101408