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Structure of the Clostridium perfringens GH89 in complex with beta-HNJNAcStructure of the Clostridium perfringens GH89 in complex with beta-HNJNAc
Structural highlights
FunctionPublication Abstract from PubMedMucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, alpha-N-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 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both alpha- and beta-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured beta-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. Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*.,Zhu S, Jagadeesh Y, Tran AT, Imaeda S, Boraston A, Alonzi DS, Poveda A, Zhang Y, Desire J, Charollais-Thoenig J, Demotz S, Kato A, Butters TD, Jimenez-Barbero J, Sollogoub M, Bleriot Y Chemistry. 2021 Jun 9. doi: 10.1002/chem.202101408. PMID:34106504[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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