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Stereochemistry and amyloid inhibition : asymmetric triplex metallohelices enantioselectively bind to Aβ peptide
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Guan, Yijia, Du, Zhi, Gao, Nan, Cao, Yue, Wang, Xiaohui, Scott, Peter, Song, Hualong, Ren, Jinsong and Qu, Xiaogang (2018) Stereochemistry and amyloid inhibition : asymmetric triplex metallohelices enantioselectively bind to Aβ peptide. Science Advances, 4 (1). eaao6718. doi:10.1126/sciadv.aao6718 ISSN 2375-2548.
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Official URL: http://dx.doi.org/10.1126/sciadv.aao6718
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.
Item Type: | Journal Article | ||||||||||||||||||||||||
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Subjects: | Q Science > QD Chemistry | ||||||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Stereochemistry, Amyloid, Peptides | ||||||||||||||||||||||||
Journal or Publication Title: | Science Advances | ||||||||||||||||||||||||
Publisher: | American Association for the Advancement of Science | ||||||||||||||||||||||||
ISSN: | 2375-2548 | ||||||||||||||||||||||||
Official Date: | 19 January 2018 | ||||||||||||||||||||||||
Dates: |
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Volume: | 4 | ||||||||||||||||||||||||
Number: | 1 | ||||||||||||||||||||||||
Number of Pages: | 10 | ||||||||||||||||||||||||
Article Number: | eaao6718 | ||||||||||||||||||||||||
DOI: | 10.1126/sciadv.aao6718 | ||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
Date of first compliant deposit: | 3 April 2018 | ||||||||||||||||||||||||
Date of first compliant Open Access: | 3 April 2018 | ||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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