{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:59:24Z","timestamp":1790974764145,"version":"4.1.0"},"reference-count":62,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2013,6,14]],"date-time":"2013-06-14T00:00:00Z","timestamp":1371168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2013,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in acid \u03b2\u2010glucocerebrosidase (GCase) lead to the accumulation of the sphingolipid glucosylceramide, thereby resulting in Gaucher disease (GD). Active\u2010site\u2010specific competitive GCase inhibitors are effective pharmacological chaperones (PCs) that act as folding agents for mutant GCase folding in the endoplasmic reticulum. In this study, we prepared a series of glucoimidazole C2\u2010substituent derivatives, and evaluated their inhibition and PC properties with GCase. A cell\u2010based assay with patient\u2010derived lymphoblasts (N370S or L444P mutations) demonstrated that administration of these compounds can significantly increase GCase activity. Interestingly, the 3,3\u2010dimethyl\u2010<jats:italic>N<\/jats:italic>\u2010phenyl\u20104\u2010amide\u20101\u2010butyl\u2010substituted moderate inhibitor <jats:bold>11<\/jats:bold> had the greatest effect on activity: 2.1\u2010fold increase in N370S lymphoblasts at 2.5 \u03bc<jats:sc>M<\/jats:sc> and 1.2\u2010fold increase in L444P at 0.5 \u03bc<jats:sc>M<\/jats:sc> following a three\u2010day incubation. Computer docking studies and a protease protection assay were used to elucidate the ligand\u2013enzyme interactions responsible for the chaperone activity of <jats:bold>11<\/jats:bold>. Western blot and immuno\u2010fluorescence assays verified restoration of GCase trafficking to the lysosome. Together, these results indicate that <jats:bold>11<\/jats:bold> is a promising PC for GD treatment and provide direct evidence of the mechanism of GCase chaperoning.<\/jats:p>","DOI":"10.1002\/cbic.201300197","type":"journal-article","created":{"date-parts":[[2013,6,14]],"date-time":"2013-06-14T08:34:43Z","timestamp":1371198883000},"page":"1239-1247","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["New Insights into the Pharmacological Chaperone Activity of C2\u2010Substituted Glucoimidazoles for the Treatment of Gaucher Disease"],"prefix":"10.1002","volume":"14","author":[{"given":"Zhonghua","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiehai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxing","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng George","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,6,14]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174447"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1423"},{"key":"e_1_2_6_3_2","unstructured":"\u201cGaucher Disease\u201d E. 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