Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aβ peptide

Stereochemistry is vital for pharmaceutical development and can determine drug efficacy. Herein, 10 pairs of asymmetric triplex metallohelix enantiomers as a library were used to screen inhibitors of amyloid β (Aβ) aggregation via a fluorescent cell–based high-throughput method. Intriguingly, Λ enantiomers show a stronger inhibition effect than Δ enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key role in the Aβ interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the Λ enantiomer to Aβ is much faster than that of the Δ enantiomer. Furthermore, studies in enzyme digestion, isothermal titration calorimetry, nuclear magnetic resonance, and computational docking demonstrate that the enantiomers bind to the central hydrophobic α-helical region of Aβ13–23, although with different modes for the Λ and Δ enantiomers. Finally, an in vivo study showed that these metallohelices extend the life span of the Caenorhabditis elegans CL2006 strain by attenuating Aβ-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer’s disease.