This title appears in the Scientific Report :
2012
Please use the identifier:
http://dx.doi.org/10.1074/jbc.M112.357665 in citations.
Discovery and structure activity relationship of small molecule inhibitors of toxic-ß--amyloid-42 fibril formation
Discovery and structure activity relationship of small molecule inhibitors of toxic-ß--amyloid-42 fibril formation
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...
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Personal Name(s): | Kroth, H. |
---|---|
Ansaloni, A. / Varisco, Y. / Jan, A. / Sreenivasachary, N. / Rezaei-Ghaleh, N. / Giriens, V. / Lohmann, S. / Pilar López-Deber, M. / Adolfsson, O. / Pihlgren, M. / Paganetti, P. / Froestl, W. / Nagel-Steger, L. / Willbold, D / Schrader, T / Zweckstetter, M. / Pfeifer, A. / Lashuel, H.A. / Muhs, A. | |
Contributing Institute: |
Strukturbiochemie; ICS-6 |
Published in: | The @journal of biological chemistry, 287 (2012) S. 34786 - 34800 |
Imprint: |
Bethesda, Md.
Soc.
2012
|
Physical Description: |
34786 - 34800 |
PubMed ID: |
22891248 |
DOI: |
10.1074/jbc.M112.357665 |
Document Type: |
Journal Article |
Research Program: |
BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung Funktion und Dysfunktion des Nervensystems |
Series Title: |
Journal of Biological Chemistry
287 |
Publikationsportal JuSER |
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. |