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All of these compounds, which were designed as glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal \u03b2\u2010glucosidase (glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di\u2010<jats:italic>O<\/jats:italic>\u2010hexyl ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di\u2010<jats:italic>O<\/jats:italic>\u2010decanoyl ester was a potent chaperone of the L444P hydrolase, capable of increasing the residual activity of the enzyme by a factor of two at a very low concentration (50\u2005n<jats:sc>M<\/jats:sc>); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat\u2010stress studies, the diether was found to be much more effective in stabilizing the wild\u2010type enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of GlcCer synthase, because such compounds could find use in the substrate reduction therapy approach to treat lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di\u2010C<jats:sub>10<\/jats:sub>\u2010ester constitute leads for the development of therapeutic agents for types\u20052 and 3 Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.<\/jats:p>","DOI":"10.1002\/cmdc.201300327","type":"journal-article","created":{"date-parts":[[2013,10,4]],"date-time":"2013-10-04T06:05:15Z","timestamp":1380866715000},"page":"1805-1817","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Glucosylceramide Mimics: Highly Potent GCase Inhibitors and Selective Pharmacological Chaperones for Mutations Associated with Types\u20051 and 2 Gaucher Disease"],"prefix":"10.1002","volume":"8","author":[{"given":"Wojciech","family":"Sch\u00f6nemann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Gallienne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Ikeda\u2010Obatake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinpei","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"G\u00f3recki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadwiga","family":"Frelek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,10,2]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.01.089"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm3008618"},{"key":"e_1_2_6_4_2","unstructured":"\u00a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.103004.142532"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.2174\/2212796810903010100"},{"key":"e_1_2_6_7_2","unstructured":"\u00a0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470517437.ch10"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900036"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.4137\/PMC.S2332"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm301557k"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2011.0370"},{"key":"e_1_2_6_13_2","unstructured":"\u00a0"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.06041.x"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-1077-0"},{"key":"e_1_2_6_16_2","first-page":"148","author":"Hughes D.","year":"2010","journal-title":"J. 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