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Chiral metallohelical complexes enantioselectively target amyloid β for treating alzheimer's disease
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Li, Meng, Howson, Suzanne E., Dong, Kai, Gao, Nan, Ren, Jinsong, Scott, Peter and Qu, Xiaogang (2014) Chiral metallohelical complexes enantioselectively target amyloid β for treating alzheimer's disease. Journal of the American Chemical Society, Volume 136 (Number 33). pp. 11655-11663. doi:10.1021/ja502789e ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/ja502789e
Abstract
Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β (Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimer’s disease (AD). Herein we report that two triple-helical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood–brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QD Chemistry R Medicine > RS Pharmacy and materia medica |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
Library of Congress Subject Headings (LCSH): | Alzheimer's disease -- Treatment, Amyloid beta-protein, Chiral drugs | ||||||||
Journal or Publication Title: | Journal of the American Chemical Society | ||||||||
Publisher: | American Chemical Society | ||||||||
ISSN: | 0002-7863 | ||||||||
Official Date: | 20 August 2014 | ||||||||
Dates: |
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Volume: | Volume 136 | ||||||||
Number: | Number 33 | ||||||||
Page Range: | pp. 11655-11663 | ||||||||
DOI: | 10.1021/ja502789e | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||
Date of first compliant deposit: | 28 December 2015 | ||||||||
Date of first compliant Open Access: | 28 December 2015 | ||||||||
Funder: | China. Guo jia ke xue ji shu bu [Ministry of Science and Technology] (CMST), Guo jia zi ran ke xue ji jin wei yuan hui (China) [National Natural Science Foundation of China] (NSFC) | ||||||||
Grant number: | 2011CB936004 (CMST), 2012CB720602 (CMST), 21210002 (NSFC), 91213302 (NSFC) |
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