Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: implications in the aggregation mechanism of beta-amyloid peptide.
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| 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.
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| Authors | Dongxiang Liu, Yechun Xu, Yu Feng, Hong Liu, Xu Shen, Kaixian Chen, Jianpeng Ma, Hualiang Jiang |
| Journal | Biochemistry (Biochemistry) Vol. 45 Issue 36 Pg. 10963-72 (Sep 12 2006) ISSN: 0006-2960 [Print] United States |
| PMID | 16953582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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