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

ABSTRACT: 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 ? (A?) aggregation via a fluorescent cell-based high-throughput method. Intriguingly, ? enantiomers show a stronger inhibition effect than ? enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key role in the A? interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the ? enantiomer to A? is much faster than that of the ? enantiomer. Furthermore, studies in enzyme digestion, isothermal titration calorimetry, nuclear magnetic resonance, and computational docking demonstrate that the enantiomers bind to the central hydrophobic ?-helical region of A?13-23, although with different modes for the ? and ? enantiomers. Finally, an in vivo study showed that these metallohelices extend the life span of the Caenorhabditis elegans CL2006 strain by attenuating A?-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer's disease.

SUBMITTER: Guan Y 

PROVIDER: S-EPMC5775025 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature