Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: Implications in the aggregation mechanism of beta-amyloid peptide
文献类型：期刊论文
| 作者 | Liu, Dongxiang ; Xu, Yechun; Feng, Yu; Liu, Hong; Shen, Xu; Chen, Kaixian; Ma, Jianpeng; Jiang, Hualiang
|
| 刊名 | BIOCHEMISTRY
 |
| 出版日期 | 2006-09-12 |
| 卷号 | 45期号:36页码:10963-10972 |
| ISSN号 | 0006-2960 |
| DOI | 10.1021/bi060955f |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | CIRCULAR-DICHROISM SPECTRA ; ALZHEIMERS-DISEASE ; A-BETA ; FIBRIL FORMATION ; PROTEIN FIBRILLOGENESIS ; OXIDATIVE STRESS ; TRANSGENIC MICE ; DRUG DISCOVERY ; CROSS-LINKING ; SOLUTION NMR |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000240251300019 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273493]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang |
| 作者单位 | 1.Rice Univ, Dept Bioengn, Houston, TX 77005 USA 2.Chinese Acad Sci, Ctr Drug Design & Discovery, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China 4.Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA |
| 推荐引用方式 GB/T 7714 | Liu, Dongxiang,Xu, Yechun,Feng, Yu,et al. Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: Implications in the aggregation mechanism of beta-amyloid peptide[J]. BIOCHEMISTRY,2006,45(36):10963-10972. |
| APA | Liu, Dongxiang.,Xu, Yechun.,Feng, Yu.,Liu, Hong.,Shen, Xu.,...&Jiang, Hualiang.(2006).Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: Implications in the aggregation mechanism of beta-amyloid peptide.BIOCHEMISTRY,45(36),10963-10972. |
| MLA | Liu, Dongxiang,et al."Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: Implications in the aggregation mechanism of beta-amyloid peptide".BIOCHEMISTRY 45.36(2006):10963-10972. |
入库方式： OAI收割
来源：上海药物研究所
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