ABSTRACT: Aa peptides cleaved from the amyloid precursor protein are the main components of senile
plaques in Alzheimers disease. Aa peptides adopt a conformation mixture of random coil, a-sheet, and
R-helix in solution, which makes it difficult to design inhibitors based on the 3D structures of Aa peptides.
By targeting the C-terminal a-sheet region of an Aa intermediate structure extracted from molecular
dynamics simulations of Aa conformational transition, a new inhibitor that abolishes Aa 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 a-sheet content of Aa peptides either by stabilizing the C-terminal a-sheet conformation or
by inducing the intermolecular a-sheet formation. It was proposed that the inhibitor prevented fibrillation
by blocking interstrand hydrogen bond formation of the pleated a-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 Aa
aggregation.