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

Heiko Kroth, Annalisa Ansaloni, Yvan Varisco, Asad Jan, Nampally Sreenivasachary, Nasrollah Rezaei-Ghaleh, Valérie Giriens, Sophie Lohmann, María Pilar López-Deber, Oskar Adolfsson, Maria Pihlgren, Paolo Paganetti, Wolfgang Froestl, Luitgard Nagel-Steger, Dieter Willbold, Thomas Schrader, Markus Zweckstetter, Andrea Pfeifer, Hilal A. Lashuel, Andreas Muhs

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)34786-34800
Number of pages15
JournalJournal of Biological Chemistry
Volume287
Issue number41
DOIs
Publication statusPublished - 5 Oct 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kroth, H., Ansaloni, A., Varisco, Y., Jan, A., Sreenivasachary, N., Rezaei-Ghaleh, N., Giriens, V., Lohmann, S., López-Deber, M. P., Adolfsson, O., Pihlgren, M., Paganetti, P., Froestl, W., Nagel-Steger, L., Willbold, D., Schrader, T., Zweckstetter, M., Pfeifer, A., Lashuel, H. A., & Muhs, A. (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. https://doi.org/10.1074/jbc.M112.357665