TY  - JOUR
AU  - Kroth, Heiko
AU  - Ansaloni, Annalisa
AU  - Varisco, Yvan
AU  - Jan, Asad
AU  - Sreenivasachary, Nampally
AU  - Rezaei-Ghaleh, Nasrollah
AU  - Giriens, Valérie
AU  - Lohmann, Sophie
AU  - López-Deber, María Pilar
AU  - Adolfsson, Oskar
AU  - Pihlgren, Maria
AU  - Paganetti, Paolo
AU  - Froestl, Wolfgang
AU  - Nagel-Steger, Luitgard
AU  - Willbold, Dieter
AU  - Schrader, Thomas
AU  - Zweckstetter, Markus
AU  - Pfeifer, Andrea
AU  - Lashuel, Hilal A
AU  - Muhs, Andreas
TI  - Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.
JO  - The journal of biological chemistry
VL  - 287
IS  - 41
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-02973
SP  - 34786-34800
PY  - 2012
AB  - 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.
KW  - Amyloid beta-Peptides: antagonists & inhibitors
KW  - Amyloid beta-Peptides: chemistry
KW  - Cell Line, Tumor
KW  - Cytotoxins: antagonists & inhibitors
KW  - Cytotoxins: chemistry
KW  - Humans
KW  - Hydrogen Bonding
KW  - Hydrophobic and Hydrophilic Interactions
KW  - Peptide Fragments: antagonists & inhibitors
KW  - Peptide Fragments: chemistry
KW  - Protein Structure, Secondary
KW  - Pyrazoles: chemistry
KW  - Structure-Activity Relationship
KW  - 3-aminopyrazole (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Cytotoxins (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Pyrazoles (NLM Chemicals)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22891248
C2  - pmc:PMC3464581
DO  - DOI:10.1074/jbc.M112.357665
UR  - https://pub.dzne.de/record/136651
ER  -