4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to β-galactosidase mutations : improved synthesis and biological investigations

Front, Sophie (Université d'Orléans & CNRS, Institut de Chimie organique et analytique (ICOA), Orléans, France) ; Almeida, Sofia (School of Engineering and Architecture (HEIA-FR), HES-SO // University of Applied Sciences Western Switzerland) ; Zoete, Vincent (SIB (Swiss Institute of Bioinformatics), Lausanne, Switzerland) ; Charollais-Thoenig, Julie (Dorphan, EPFL Innovation Park, Lausanne, Switzerland) ; Gallienne, Estelle (Université d'Orléans & CNRS, Institut de Chimie organique et analytique (ICOA), Orléans, France) ; Marmy, Céline (School of Engineering and Architecture (HEIA-FR), HES-SO // University of Applied Sciences Western Switzerland) ; Pilloud, Vincent (School of Engineering and Architecture (HEIA-FR), HES-SO // University of Applied Sciences Western Switzerland) ; Marti, Roger (School of Engineering and Architecture (HEIA-FR), HES-SO // University of Applied Sciences Western Switzerland) ; Wood, Tim (Greenwood Genetic Center, Greenwood, USA) ; Martin, Olivier R. (Université d'Orléans & CNRS, Institut de Chimie organique et analytique (ICOA), Orléans, France) ; Demotz, Stéphane (Dorphan, EPFL Innovation Park, Lausanne, Switzerland)

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated β-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring β-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring β-galactosidase mutations sensitive to pharmacological chaperoning.


Article Type:
scientifique
Faculty:
Ingénierie et Architecture
School:
HEIA-FR
Institute:
ChemTech - Institut des technologies chimiques
Subject(s):
Ingénierie
Date:
2018-11
Pagination:
8 p.
Published in:
Bioorganic & Medicinal Chemistry
Numeration (vol. no.):
2018, vol. 26, no. 20, pp. 5462-5469
DOI:
ISSN:
0968-0896
Appears in Collection:

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 Record created 2019-01-08, last modified 2019-01-22

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