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Sci Adv. 2018 Jan 19;4(1):eaao6718. doi: 10.1126/sciadv.aao6718. eCollection 2018 Jan.

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

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Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
University of Chinese Academy of Sciences, Beijing 100039, China.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.


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.

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