Iminosugar-C-glycosides work as pharmacological chaperones of NAGLU, a glycosidase involved in MPS IIIB rare disease
| Autor: | Jérôme Désiré, Yves Blériot, Atsushi Kato, Dominic S. Alonzi, Jesús Jiménez-Barbero, Anh Tuan Tran, Julie Charollais-Thoenig, Yongmin Zhang, Matthieu Sollogoub, Alisdair B. Boraston, Yerri Jagadeesh, Terry D. Butters, Shuki Imaeda, Stéphane Demotz, Sha Zhu, Ana Poveda |
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| Přispěvatelé: | Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Victoria [Canada] (UVIC), Department of Biochemistry [Oxford], University of Oxford [Oxford], Cell Biology and Stem Cells Unit (CICbioGUNE), Technologic Park of Bizkaia, Dorphan, CIC BioGUNE, CIC Spain, Synthèse Organique (E5), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Toyama |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Mutant
Iminosugar 01 natural sciences Catalysis law.invention Mucopolysaccharidosis III 03 medical and health sciences chemistry.chemical_compound Rare Diseases law Acetylglucosaminidase medicine iminosugars Humans [CHIM]Chemical Sciences Glycoside hydrolase Glycosides 030304 developmental biology X-ray crystallography chemistry.chemical_classification 0303 health sciences 010405 organic chemistry Organic Chemistry Glycoside General Chemistry Heparan sulfate 0104 chemical sciences 3. Good health pharmacological chaperone Pharmacological chaperone Enzyme chemistry Biochemistry glycosidase Recombinant DNA medicine.drug |
| Zdroj: | Chemistry-A European Journal Chemistry-A European Journal, Wiley-VCH Verlag, 2021, ⟨10.1002/chem.202101408⟩ |
| ISSN: | 0947-6539 1521-3765 |
| Popis: | International audience; Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, aN -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 six-membered iminosugar-C-glycosides mimicking N-acetyl-Dglucosamine and bearing various pseudo-anomeric substituents of both a-and b-configuration. Elaboration with the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the nonfunctionalized and wrongly configured b-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. |
| Databáze: | OpenAIRE |
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