title: The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-β peptides.
abstract: Known γ-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 γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ 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 γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer's disease.
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiling
authors.initials: X
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Microbial Metabolism &School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Microbial Metabolism &School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D025442:Dihydroergocristine / Q000494:pharmacology*; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D051880:Receptors, Notch; D025442:Dihydroergocristine; D053829:Amyloid Precursor Protein Secretases