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Jan Asad

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

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DOI

  • Heiko Kroth, AC Immune SA, PSE Building B, Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
  • ,
  • 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

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.

OriginalsprogEngelsk
TidsskriftThe Journal of biological chemistry
Vol/bind287
Nummer41
Sider (fra-til)34786-800
Antal sider15
DOI
StatusUdgivet - 2012

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