Iminosugar <i>C</i> ‐Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to toxic accumulation heparan sulfate. Herein we explored pharmacological chaperone approach enhance residual activity NAGLU in patient fibroblasts. Capitalizing on three-dimensional structures two modest homoiminosugar-based inhibitors complex with bacterial homolog NAGLU, CpGH89, have synthesized library 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents both α- β-configuration. Elaboration aglycon moiety results low micromolar selective human recombinant but surprisingly it non-functionalized wrongly configured β-homoiminosugar that was proved act as most promising chaperone, promoting 2.4 fold enhancement mutant at its optimal concentration.