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Iminosugar-C-glycosides work as pharmacological chaperones of NAGLU, a glycosidase involved in MPS IIIB rare disease

Abstract : 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.
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https://hal.sorbonne-universite.fr/hal-03256952
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Submitted on : Thursday, June 10, 2021 - 3:33:44 PM
Last modification on : Tuesday, July 13, 2021 - 3:27:24 AM

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Sha Zhu, Yerri Jagadeesh, Anh Tran, Alisdair Boraston, Dominic Alonzi, et al.. Iminosugar-C-glycosides work as pharmacological chaperones of NAGLU, a glycosidase involved in MPS IIIB rare disease. Chemistry - A European Journal, Wiley-VCH Verlag, 2021, ⟨10.1002/chem.202101408⟩. ⟨hal-03256952⟩

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