Title
Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aβ peptide
Author
Yijia Guan, Zhi Du, Nan Gao, Yue Cao, Xiaohui Wang, Peter Scott, Hualong Song, Jinsong Ren, Xiaogang Qu
Year
2018
Journal
Science Advances
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 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.
Instrument
J-810, FP-6500
Keywords
Circular dichroism, Secondary structure, Stereochemistry, Chemical stability, Ligand binding, Aggregation, Biochemistry, Pharmaceutical, Fluorescence, Protein structure, Aggregation, Kinetics