title: Chiral metallohelical complexes enantioselectively target amyloid β for treating Alzheimer's disease.
abstract: Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β (Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimer's disease (AD). Herein we report that two triple-helical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.
authors: Laboratory of Chemical Biology, Division of Biological Inorganic Chemistry, State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences , Changchun, Jilin 130022, China.
authors: Meng
authors: M
authors: Li
authors: Suzanne E
authors: SE
authors: Howson
authors: Kai
authors: K
authors: Dong
authors: Nan
authors: N
authors: Gao
authors: Jinsong
authors: J
authors: Ren
authors: Peter
authors: P
authors: Scott
authors: Xiaogang
authors: X
authors: Qu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase