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Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1\u2010deoxynojirimycin (DNJ) analogue (3.3\u2010fold increase at 10 \u03bc<jats:sc>M<\/jats:sc>). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0\u2010fold instead of 2.4\u2010fold) at a cellular concentration (1 \u03bc<jats:sc>M<\/jats:sc>) reduced by one order of magnitude.<\/jats:p>","DOI":"10.1002\/cbic.201300442","type":"journal-article","created":{"date-parts":[[2013,12,20]],"date-time":"2013-12-20T13:24:08Z","timestamp":1387545848000},"page":"309-319","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["A Systematic Investigation of Iminosugar Click Clusters as Pharmacological Chaperones for the Treatment of Gaucher Disease"],"prefix":"10.1002","volume":"15","author":[{"given":"Antoine","family":"Joosten","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Decroocq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"de Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9my P.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile","family":"Etam\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bodlenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry D.","family":"Butters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Compain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,12,20]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"For reviews see:"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200390045"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2004.00232.x"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/jbiol186"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22856"},{"key":"e_1_2_6_6_2","unstructured":"\u00a0"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470517437.ch10"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(03)00158-5"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2008.009"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.06042.x"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.4137\/PMC.S2332"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900036"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:BOLI.0000031101.12838.c6"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728214.2010.498580"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5437-0"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2011.0370"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/157340812800228955"},{"key":"e_1_2_6_18_2","unstructured":"\u00a0"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2011.569162"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm301557k"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.13.14"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470517437.ch14"},{"key":"e_1_2_6_23_2","unstructured":"\u00a0"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1042\/bst0280150"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0301-4"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3757(19990601)111:11<1632::AID-ANGE1632>3.0.CO;2-A"},{"key":"e_1_2_6_26_3","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3773(19990601)38:11<1532::AID-ANIE1532>3.0.CO;2-U"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.60.070191.001353"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.05.027"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:GLYC.0000046272.38480.ef"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200902620"},{"key":"e_1_2_6_30_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200902620"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201208152"},{"key":"e_1_2_6_32_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1182\/asheducation.V2012.1.13.3797921","volume":"2012","author":"Grabowski G. 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relative inhibition potency over the corresponding monovalent analogue per iminosugar ligand is superior to one; see:"},{"key":"e_1_2_6_98_2","doi-asserted-by":"publisher","DOI":"10.1039\/C0OB00389A"},{"key":"e_1_2_6_99_2","doi-asserted-by":"publisher","DOI":"10.1039\/b413971b"},{"key":"e_1_2_6_100_2","unstructured":"All attempts to prepare a pure sample of the tetravalent DIX analogue of14with a C9linker proved unsuccessful. Because of isomerization side\u2010reactions of C\uf8feC double bonds in the reactants during the key cross\u2010metathesis step [29]an inseparable mixture of the expected azido iminosugar precursor along with the two corresponding analogues incorporating a C8or a C10alkyl spacer was obtained as judged by NMR and MS analysis. To have an idea of the impact of longer alkyl spacers on GCase binding affinity and chaperoning activity we nevertheless synthesized the corresponding hetero\u2010tetravalent analogues. Interestingly this mixture of tetravalent DIX clusters with a distribution of C8to C10alkyl spacers was found to display strong inhibition toward GCase [Ki=(0.7\u00b10.6) nM; IC50=(2.1\u00b10.1) nM] but no significant chaperoning activity."},{"key":"e_1_2_6_101_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.11.056"},{"key":"e_1_2_6_102_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo201125x"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcbic.201300442","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.201300442","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T09:08:32Z","timestamp":1760260112000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.201300442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,20]]},"references-count":107,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,1,24]]}},"alternative-id":["10.1002\/cbic.201300442"],"URL":"https:\/\/doi.org\/10.1002\/cbic.201300442","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,20]]},"assertion":[{"value":"2013-07-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-12-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}