000216647 001__ 216647
000216647 005__ 20190317000410.0
000216647 0247_ $$2doi$$a10.1038/srep16541
000216647 022__ $$a2045-2322
000216647 02470 $$2ISI$$a000364668900001
000216647 037__ $$aARTICLE
000216647 245__ $$aThe FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-beta peptides
000216647 260__ $$bNature Publishing Group$$c2015$$aLondon
000216647 269__ $$a2015
000216647 300__ $$a11
000216647 336__ $$aJournal Articles
000216647 520__ $$aKnown gamma-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of gamma-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (A beta) and that have better pharmacokinetics and an improved safety profile, we completed a screen of similar to 400 natural products by using cell-based and cell-free gamma-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA-(Food and Drug Administration)-approved drug, to be a direct inhibitor of gamma-secretase. Micromolar concentrations of DHEC substantially reduced A beta levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting gamma-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to gamma-secretase and Nicastrin, with equilibrium dissociation constants (K-d) of 25.7 nM and 9.8 mu M, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of gamma-secretase but also a candidate for drug repositioning in Alzheimer's disease.
000216647 700__ $$uShanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Minist Educ, Key Lab Syst Biomed, Shanghai 200030, Peoples R China$$aLei, Xiling
000216647 700__ $$uShanghai Jiao Tong Univ, State Key Lab Microbial Metab, Shanghai 200030, Peoples R China$$aYu, Jing
000216647 700__ $$uShanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Minist Educ, Key Lab Syst Biomed, Shanghai 200030, Peoples R China$$aNiu, Qi
000216647 700__ $$uShanghai Jiao Tong Univ, State Key Lab Microbial Metab, Shanghai 200030, Peoples R China$$aLiu, Jianhua
000216647 700__ $$0244196$$g171915$$aFraering, Patrick C.
000216647 700__ $$uShanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Minist Educ, Key Lab Syst Biomed, Shanghai 200030, Peoples R China$$aWu, Fang$$g182412$$0244195
000216647 773__ $$j5$$tScientific Reports$$q16541
000216647 8564_ $$uhttps://infoscience.epfl.ch/record/216647/files/srep16541.pdf$$zPublisher's version$$s1422700$$yPublisher's version
000216647 909C0 $$xU11281$$0252048$$pCMSN
000216647 909CO $$qGLOBAL_SET$$particle$$ooai:infoscience.tind.io:216647
000216647 917Z8 $$x182396
000216647 937__ $$aEPFL-ARTICLE-216647
000216647 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000216647 980__ $$aARTICLE