%0 Journal Article
%A Kroth, Heiko
%A Ansaloni, Annalisa
%A Varisco, Yvan
%A Jan, Asad
%A Sreenivasachary, Nampally
%A Rezaei-Ghaleh, Nasrollah
%A Giriens, Valérie
%A Lohmann, Sophie
%A López-Deber, María Pilar
%A Adolfsson, Oskar
%A Pihlgren, Maria
%A Paganetti, Paolo
%A Froestl, Wolfgang
%A Nagel-Steger, Luitgard
%A Willbold, Dieter
%A Schrader, Thomas
%A Zweckstetter, Markus
%A Pfeifer, Andrea
%A Lashuel, Hilal A
%A Muhs, Andreas
%T Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.
%J The journal of biological chemistry
%V 287
%N 41
%@ 0021-9258
%C Bethesda, Md.
%I Soc.60645
%M DZNE-2020-02973
%P 34786-34800
%D 2012
%X 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.
%K Amyloid beta-Peptides: antagonists & inhibitors
%K Amyloid beta-Peptides: chemistry
%K Cell Line, Tumor
%K Cytotoxins: antagonists & inhibitors
%K Cytotoxins: chemistry
%K Humans
%K Hydrogen Bonding
%K Hydrophobic and Hydrophilic Interactions
%K Peptide Fragments: antagonists & inhibitors
%K Peptide Fragments: chemistry
%K Protein Structure, Secondary
%K Pyrazoles: chemistry
%K Structure-Activity Relationship
%K 3-aminopyrazole (NLM Chemicals)
%K Amyloid beta-Peptides (NLM Chemicals)
%K Cytotoxins (NLM Chemicals)
%K Peptide Fragments (NLM Chemicals)
%K Pyrazoles (NLM Chemicals)
%K amyloid beta-protein (1-42) (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:22891248
%2 pmc:PMC3464581
%R 10.1074/jbc.M112.357665
%U https://pub.dzne.de/record/136651