Tranilast Binds to A尾 Monomers and Promotes A尾 Fibrillation

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• 作者：Christopher R. Connors ; David J. Rosenman ; Dahabada H. J. Lopes ; Shivina Mittal ; Gal Bitan ; Mirco Sorci ; Georges Belfort ; Angel Garcia ; Chunyu Wang
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：June 11, 2013
• 年：2013
• 卷：52
• 期：23
• 页码：3995-4002
• 全文大小：458K
• 年卷期：v.52,no.23(June 11, 2013)
• ISSN：1520-4995

文摘

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer鈥檚 disease (AD), in which amyloid 尾-protein (A尾) plays a key pathogenic role. We used solution NMR to determine that tranilast binds to A尾40 monomers with 300 渭M affinity. Remarkably, tranilast increases A尾40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time. Tranilast likely promotes fibrillation by shifting A尾 monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the A尾鈥搕ranilast interaction. These data suggest that AD may be a potential complication for tranilast usage in elderly patients.