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Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three\u2010dimensional structures of two modest homoiminosugar\u2010based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar <jats:italic>C<\/jats:italic>\u2010glycosides mimicking <jats:italic>N<\/jats:italic>\u2010acetyl\u2010D\u2010glucosamine and bearing various pseudo\u2010anomeric substituents of both \u03b1\u2010 and \u03b2\u2010configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non\u2010functionalized and wrongly configured \u03b2\u2010homoiminosugar 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.<\/jats:p>","DOI":"10.1002\/chem.202101408","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T09:02:50Z","timestamp":1623229370000},"page":"11291-11297","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Iminosugar <i>C<\/i>\u2010Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**"],"prefix":"10.1002","volume":"27","author":[{"given":"Sha","family":"Zhu","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9 CNRS, Institut Parisien de Chimie Mol\u00e9culaire UMR 8232  4 place Jussieu 75005 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yerri","family":"Jagadeesh","sequence":"additional","affiliation":[{"name":"Glycochemistry Group of \u201cOrgaSynth\u201d Team IC2MP, UMR-CNRS 7285 Universit\u00e9 de Poitiers  4 rue Michel Brunet 86073 Poitiers Cedex 9 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh Tuan","family":"Tran","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9 CNRS, Institut Parisien de Chimie Mol\u00e9culaire UMR 8232  4 place Jussieu 75005 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuki","family":"Imaeda","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy University of Toyama  2630 Sugitani Toyama 930-0194 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6417-0592","authenticated-orcid":false,"given":"Alisdair","family":"Boraston","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology University of Victoria  P.O. 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