title: Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: implications in the aggregation mechanism of beta-amyloid peptide.
abstract: Abeta peptides cleaved from the amyloid precursor protein are the main components of senile plaques in Alzheimer's disease. Abeta peptides adopt a conformation mixture of random coil, beta-sheet, and alpha-helix in solution, which makes it difficult to design inhibitors based on the 3D structures of Abeta peptides. By targeting the C-terminal beta-sheet region of an Abeta intermediate structure extracted from molecular dynamics simulations of Abeta conformational transition, a new inhibitor that abolishes Abeta fibrillation was discovered using virtual screening in conjunction with thioflavin T fluorescence assay and atomic force microscopy determination. Circular dichroism spectroscopy demonstrated that the binding of the inhibitor increased the beta-sheet content of Abeta peptides either by stabilizing the C-terminal beta-sheet conformation or by inducing the intermolecular beta-sheet formation. It was proposed that the inhibitor prevented fibrillation by blocking interstrand hydrogen bond formation of the pleated beta-sheet structure commonly found in amyloid fibrils. The study not only provided a strategy for inhibitor design based on the flexible structures of amyloid peptides but also revealed some clues to understanding the molecular events involved in Abeta aggregation.
authors.affiliation: Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. dxl@mail.shcnc.ac.cn
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000682:Amyloid / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D052160:Benzothiazoles; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D002942:Circular Dichroism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005453:Fluorescence; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D009025:Morpholines / Q000494:pharmacology*; D011487:Protein Conformation; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D001559:Benzhydryl Compounds; D052160:Benzothiazoles; C514245:DC-AB1; D009025:Morpholines; D013844:Thiazoles; C009462:thioflavin T