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

MPG-Autoren
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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

Volltexte (frei zugänglich)

1589137.pdf
(Verlagsversion), 4MB

Ergänzendes Material (frei zugänglich)

1589137-SI.pdf
(Ergänzendes Material), 857KB

Zitation

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.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-000E-7300-D
Zusammenfassung
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.