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

International audienceMucopolysaccharidosis 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