Inhibitor discovery targeting the intermediate structure of β-amyloid peptide on the conformational transition pathway:: Implications in the aggregation mechanism of β-amyloid peptide

A beta peptides cleaved from the amyloid precursor protein are the main components of senile plaques in Alzheimer's disease. A beta 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 A beta peptides. By targeting the C-terminal beta-sheet region of an A beta intermediate structure extracted from molecular dynamics simulations of A, conformational transition, a new inhibitor that abolishes A beta 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 A beta 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 A beta aggregation.