Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aß peptide.
Sci Adv
; 4(1): eaao6718, 2018 01.
Article
em En
| MEDLINE
| ID: mdl-29372182
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 ß (Aß) 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 Aß interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the Λ enantiomer to Aß 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 Aß13-23, 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 Aß-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer's disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Complexos de Coordenação
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Doença de Alzheimer
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Simulação de Acoplamento Molecular
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article