Discovery and structure activity relationship of small molecule inhibitors of toxic β-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 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.
AC Immune SA, PSE Building B, Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Heiko
H
Kroth
Annalisa
A
Ansaloni
Yvan
Y
Varisco
Asad
A
Jan
Nampally
N
Sreenivasachary
Nasrollah
N
Rezaei-Ghaleh
Valérie
V
Giriens
Sophie
S
Lohmann
María Pilar
MP
López-Deber
Oskar
O
Adolfsson
Maria
M
Pihlgren
Paolo
P
Paganetti
Wolfgang
W
Froestl
Luitgard
L
Nagel-Steger
Dieter
D
Willbold
Thomas
T
Schrader
Markus
M
Zweckstetter
Andrea
A
Pfeifer
Hilal A
HA
Lashuel
Andreas
A
Muhs
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
C436945:3-aminopyrazole; D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D010446:Peptide Fragments; D011720:Pyrazoles; C075222:amyloid beta-protein (1-42)