Monitoring and Inhibition of Insulin Fibrillation by a Small Organic Fluorogen with Aggregation-Induced Emission Characteristics

详细信息    查看全文

• 作者：Yuning Hong ; Luming Meng ; Sijie Chen ; Chris Wai Tung Leung ; Lin-Tai Da ; Mahtab Faisal ; Daniel-Adriano Silva ; Jianzhao Liu ; Jacky Wing Yip Lam ; Xuhui Huang ; Ben Zhong Tang
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：January 25, 2012
• 年：2012
• 卷：134
• 期：3
• 页码：1680-1689
• 全文大小：556K
• 年卷期：v.134,no.3(January 25, 2012)
• ISSN：1520-5126

文摘

Amyloid fibrillation of proteins is associated with a great variety of pathologic conditions. Development of new molecules that can monitor amyloidosis kinetics and inhibit fibril formation is of great diagnostic and therapeutic value. In this work, we have developed a biocompatible molecule that functions as an ex situ monitor and an in situ inhibitor for protein fibrillation, using insulin as a model protein. 1,2-Bis[4-(3-sulfonatopropoxyl)phenyl]-1,2-diphenylethene salt (BSPOTPE) is nonemissive when it is dissolved with native insulin in an incubation buffer but starts to fluoresce when it is mixed with preformed insulin fibril, enabling ex situ monitoring of amyloidogenesis kinetics and high-contrast fluorescence imaging of protein fibrils. Premixing BSPOTPE with insulin, on the other hand, inhibits the nucleation process and impedes the protofibril formation. Increasing the dose of BSPOTPE boosts its inhibitory potency. Theoretical modeling using molecular dynamics simulations and docking reveals that BSPOTPE is prone to binding to partially unfolded insulin through hydrophobic interaction of the phenyl rings of BSPOTPE with the exposed hydrophobic residues of insulin. Such binding is assumed to have stabilized the partially unfolded insulin and obstructed the formation of the critical oligomeric species in the protein fibrillogenesis process.