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  Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation

Kroth, H., Ansaloni, A., Varisco, Y., Jan, A., Sreenivasachary, N., Rezaei-Ghaleh, N., et al. (2012). Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. Journal of Biological Chemistry, 287(41), 34786-34800. doi:10.1074/jbc.M112.357665.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-7300-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-D0B7-7
Genre: Journal Article

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 Creators:
Kroth, H., Author
Ansaloni, A., Author
Varisco, Y., Author
Jan, A., Author
Sreenivasachary, N., Author
Rezaei-Ghaleh, N., Author
Giriens, V., Author
Lohmann, S., Author
López-Deber, M. P., Author
Adolfsson, O., Author
Pihlgren, M., Author
Paganetti, P., Author
Froestl, W., Author
Nagel-Steger, L., Author
Willbold, D., Author
Schrader, T., Author
Zweckstetter, M.1, Author              
Pfeifer, A., Author
Lashuel, H. A., Author
Muhs, A., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Alzheimer Disease; Medicinal Chemistry; Organic Chemistry; Protein Aggregation; Small Molecules; β-Amyloid Fibrillization
 Abstract: Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.

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Language(s): eng - English
 Dates: 2012-08-132012-10-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M112.357665
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 287 (41) Sequence Number: - Start / End Page: 34786 - 34800 Identifier: ISSN: 0021-9258