A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42).
Inhibition of oligomeric amyloid beta (Abeta) peptide or fibril formation has emerged as a major therapeutic target for developing new drugs for Alzheimer's disease. We focused on developing inhibitors by synthesizing hybrid molecules of ferulic acid and styryl benzene, which has been known as a fibril binder. Initially, cell-based assay was carried out to evaluate the effective compound. A selected effector, 1, alleviated the Abeta-induced neuronal toxicity in differentiated SH-SY5Y human neuroblastoma cells. The effector could also inhibit Abeta fibril formation, monitored by thioflavin T fluorescence intensity assay and transmitted electron microscopic images. A strong binding affinity of 1 to non-fibrous monomer-like Abeta, which was immobilized to a surface chip, was measured using a surface plasmon resonance technique. The data suggest that the effector shifts the equilibrium of multimeric Abeta, inhibiting the pathogenic oligomer or fibril formation.
Lee
Kyung Hyun
KH
Department of Chemistry and Education, Seoul National University, Seoul 151-742, Republic of Korea.
Shin
Byung Hee
BH
Shin
Kye Jung
KJ
Kim
Dong Jin
DJ
Yu
Jaehoon
J
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D001554:Benzene / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D003373:Coumaric Acids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C004999:ferulic acid; D001554:Benzene