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Iminosugar C ‐Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease **
Author(s) -
Zhu Sha,
Jagadeesh Yerri,
Tran Anh Tuan,
Imaeda Shuki,
Boraston Alisdair,
Alonzi Dominic S.,
Poveda Ana,
Zhang Yongmin,
Désiré Jérôme,
CharollaisThoenig Julie,
Demotz Stéphane,
Kato Atsushi,
Butters Terry D.,
JiménezBarbero Jesús,
Sollogoub Matthieu,
Blériot Yves
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202101408
Subject(s) - iminosugar , chemistry , glycoside hydrolase , chaperone (clinical) , biochemistry , recombinant dna , enzyme , moiety , stereochemistry , medicine , pathology , gene
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.