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Herein, we describe a series of novel tripartite structures, their full characterization by NMR spectroscopy and mass spectrometry, and the analysis of their biological activity in cell\u2010based assays. The tripartite structure concept is applicable to different pharmacophores, and the potency in terms of \u03b2\u2010secretase inhibition can be optimized by adjusting the spacer length to achieve an optimal distance of the inhibitor from the lipid bilayer. A tripartite structure containing a transition\u2010state mimic inhibitor was found to be less potent on A\u03b2 generation from Swedish\u2010mutant amyloid precursor protein (APP) than from the wild\u2010type protein. Moreover, our observations suggest that specific variants of A\u03b2 are generated from wild\u2010type APP but not from Swedish\u2010mutant APP and are resistant to \u03b2\u2010secretase inhibition. Efficient inhibition of A\u03b2 secretion by tripartite structures in the absence of appreciable neurotoxicity was confirmed in a primary neuronal cell culture, thus further supporting the concept.<\/jats:p>","DOI":"10.1002\/chem.201002878","type":"journal-article","created":{"date-parts":[[2010,12,3]],"date-time":"2010-12-03T07:09:21Z","timestamp":1291360161000},"page":"14412-14423","source":"Crossref","is-referenced-by-count":23,"title":["Structural Design, Solid\u2010Phase Synthesis and Activity of Membrane\u2010Anchored \u03b2\u2010Secretase Inhibitors on A\u03b2 Generation from Wild\u2010Type and Swedish\u2010Mutant APP"],"prefix":"10.1002","volume":"16","author":[{"given":"Heinke","family":"Schieb","sequence":"first","affiliation":[]},{"given":"Sebastian","family":"Weidlich","sequence":"additional","affiliation":[]},{"given":"Georg","family":"Schlechtingen","sequence":"additional","affiliation":[]},{"given":"Philipp","family":"Linning","sequence":"additional","affiliation":[]},{"given":"Gary","family":"Jennings","sequence":"additional","affiliation":[]},{"given":"Margit","family":"Gruner","sequence":"additional","affiliation":[]},{"given":"Jens","family":"Wiltfang","sequence":"additional","affiliation":[]},{"given":"Hans\u2010Wolfgang","family":"Klafki","sequence":"additional","affiliation":[]},{"given":"Hans\u2010Joachim","family":"Kn\u00f6lker","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2010,12,3]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/35043065"},{"key":"e_1_2_6_2_2","unstructured":"\u00a0"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.1999.0811"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.4.1456"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/990114"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5440.735"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/990107"},{"key":"e_1_2_6_8_2","unstructured":"\u00a0"},{"key":"e_1_2_6_9_2","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1242\/jcs.113.11.1857","volume":"113","author":"De Strooper B.","year":"2000","journal-title":"J. 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