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

37 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
Externally publishedYes

Fingerprint

Poisons
Structure-Activity Relationship
Amyloid
Self assembly
Molecules
Toxicity
Assays
Hydrophobic and Hydrophilic Interactions
Scaffolds
Conformations
Hydrogen
Hydrogen bonds
Alzheimer Disease
Substitution reactions
Agglomeration
Amino Acids
Peptides
3-aminopyrazole
In Vitro Techniques
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Kroth, H., Ansaloni, A., Varisco, Y., Jan, A., Sreenivasachary, N., Rezaei-Ghaleh, N., ... 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

Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. / Kroth, Heiko; Ansaloni, Annalisa; Varisco, Yvan; Jan, Asad; Sreenivasachary, Nampally; Rezaei-Ghaleh, Nasrollah; Giriens, Valérie; Lohmann, Sophie; López-Deber, María Pilar; Adolfsson, Oskar; Pihlgren, Maria; Paganetti, Paolo; Froestl, Wolfgang; Nagel-Steger, Luitgard; Willbold, Dieter; Schrader, Thomas; Zweckstetter, Markus; Pfeifer, Andrea; Lashuel, Hilal A.; Muhs, Andreas.

In: Journal of Biological Chemistry, Vol. 287, No. 41, 05.10.2012, p. 34786-34800.

Research output: Contribution to journalArticle

Kroth, H, Ansaloni, A, Varisco, Y, Jan, A, Sreenivasachary, N, Rezaei-Ghaleh, N, Giriens, V, Lohmann, S, López-Deber, MP, Adolfsson, O, Pihlgren, M, Paganetti, P, Froestl, W, Nagel-Steger, L, Willbold, D, Schrader, T, Zweckstetter, M, Pfeifer, A, Lashuel, HA & Muhs, A 2012, 'Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation', Journal of Biological Chemistry, vol. 287, no. 41, pp. 34786-34800. https://doi.org/10.1074/jbc.M112.357665
Kroth, Heiko ; Ansaloni, Annalisa ; Varisco, Yvan ; Jan, Asad ; Sreenivasachary, Nampally ; Rezaei-Ghaleh, Nasrollah ; Giriens, Valérie ; Lohmann, Sophie ; López-Deber, María Pilar ; Adolfsson, Oskar ; Pihlgren, Maria ; Paganetti, Paolo ; Froestl, Wolfgang ; Nagel-Steger, Luitgard ; Willbold, Dieter ; Schrader, Thomas ; Zweckstetter, Markus ; Pfeifer, Andrea ; Lashuel, Hilal A. ; Muhs, Andreas. / Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 41. pp. 34786-34800.
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