A new class of aggregation inhibitor of amyloid-β peptide based on an O-acyl isopeptide.
Inhibition of amyloid β peptide (Aβ) aggregation is a potential therapeutic approach to treat Alzheimer's disease. We report that an O-acyl isopeptide of Aβ1-42 (1) containing an ester bond at the Gly(25)-Ser(26) moiety inhibits Aβ1-42 fibril formation at equimolar ratio. Inhibitory activity was retained by an N-Me-β-Ala(26) derivative (2), in which the ester of 1 was replaced with N-methyl amide to improve chemical stability at physiological pH. Inhibition was verified by fluorescence anisotropy, Western blot, and atomic force microscopy. This report suggests a new class of Aβ aggregation inhibitor based on modification of Aβ1-42 at Gly(25)-Ser(26).
Department of Pharmaceutical Manufacturing Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan; Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Hiroyuki
H
Kawashima
Youhei
Y
Sohma
Tomoya
T
Nakanishi
Hitomi
H
Kitamura
Hidehito
H
Mukai
Masayuki
M
Yamashita
Kenichi
K
Akaji
Yoshiaki
Y
Kiso
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004952:Esters; D005454:Fluorescence Polarization; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
D016229:Amyloid beta-Peptides; D004952:Esters; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42)
AD; Aggregation; Alzheimer; Alzheimer’s disease; Amyloid; Aβ; DIC; DMF; DMSO; FAM; HOBt; HPLC; Inhibitor; Isopeptide; MALDI; MS; N,N-dimethylformamide; N,N′-diisopropylcarbodiimide; N-hydroxybenzotriazole; NDGA; TFA; TOF; UV; amyloid β peptide; carboxyfluorescein; dimethyl sulfoxide; high-performance liquid chromatography; kDa; kilodalton of mass; mass spectrometry; matrix-assisted laser desorption ionization; nordihydroguaiaretic acid; time of flight; trifluroacetic acid; ultra-violet