Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

• Published in: The Journal of biological chemistry 2012-10, Vol.287 (41), p.34786-34800
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer Disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Cell Line, Tumor; Cytotoxins - antagonists & inhibitors; Cytotoxins - chemistry; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Medicinal Chemistry; Molecular Bases of Disease; Organic Chemistry; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Protein Aggregation; Protein Structure, Secondary; Pyrazoles - chemistry; Small Molecules; Structure-Activity Relationship; β-Amyloid Fibrillization
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.357665

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. Background: Self-aggregation of β-amyloid plays an important role in the pathogenesis of Alzheimer disease. Results: Small molecule inhibitors of β-amyloid fibril formation reduce β-amyloid mediated cell toxicity. Conclusion: Rational design led to the successful development of small molecule inhibitors of β-amyloid oligomerization and toxicity. Significance: Small molecules targeting β-amyloid misfolding may provide new treatments for Alzheimer disease.