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

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

  • Chemistry. 2021 Aug 5;27(44):11291-11297. doi: 10.1002/chem.202101408.
Sha Zhu 1,  Yerri Jagadeesh 2,  Anh Tuan Tran 1,  Shuki Imaeda 3,  Alisdair Boraston 4,  Dominic S Alonzi 5,  Ana Poveda 6,  Yongmin Zhang 1,  Jérôme Désiré 2,  Julie Charollais-Thoenig 7,  Stéphane Demotz 7,  Atsushi Kato 3,  Terry D Butters 5,  Jesús Jiménez-Barbero 6,  Matthieu Sollogoub 1,  Yves Blériot 2
Affiliations

Affiliations

  • 1 Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 place Jussieu, 75005, Paris, France.
  • 2 Glycochemistry Group of "OrgaSynth" Team, IC2MP, UMR-CNRS 7285, Université de Poitiers, 4 rue Michel Brunet, 86073, Poitiers Cedex 9, France.
  • 3 Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
  • 4 Department of Biochemistry and Microbiology, University of Victoria, P.O. Box 3055, Station CSC V8W 3P6, Victoria, BC, Canada.
  • 5 Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K.
  • 6 CIC bioGUNE, Bizkaia Technological Park, Building 801A-1°, 48160, Derio-Bizkaia, Spain.
  • 7 Dorphan SA, EPFL Innovation Park, 1015, Lausanne, Switzerland.
PMID: 34106504 DOI: 10.1002/chem.202101408
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.

Keywords

X-ray crystallography; glycosidase; iminosugars; pharmacological chaperones.

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