Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer's Disease.

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 triplehelical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-/βinhibitors. Through targeting α /β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit A/β 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 A/β 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 A/β aggregation and opens a new avenue for design and screening of chiral agents as A/β inhibitors against AD. [ABSTRACT FROM AUTHOR]