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

Chemistry (Weinheim an der Bergstrasse, Germany) 2021 Aug 05

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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. © 2021 Wiley-VCH GmbH.

Citation

Sha Zhu, Yerri Jagadeesh, Anh Tuan Tran, Shuki Imaeda, Alisdair Boraston, Dominic S Alonzi, Ana Poveda, Yongmin Zhang, Jérôme Désiré, Julie Charollais-Thoenig, Stéphane Demotz, Atsushi Kato, Terry D Butters, Jesús Jiménez-Barbero, Matthieu Sollogoub, Yves Blériot. Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*. Chemistry (Weinheim an der Bergstrasse, Germany). 2021 Aug 05;27(44):11291-11297