Molecular Design for Dual Modulation Effect of Amyloid Protein Aggregation

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• 作者：Lijuan Zhu ; Yang Song ; Pin-Nan Cheng ; Jeffrey S. Moore
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：July 1, 2015
• 年：2015
• 卷：137
• 期：25
• 页码：8062-8068
• 全文大小：585K
• ISSN：1520-5126

文摘

Modulation of protein self-assembly has been a powerful strategy for controlling and understanding amyloid protein aggregation. Most modulators of amyloid aggregation only involve simple inhibition or acceleration. Here we report a new multivalent molecular motif, the polyethylenimine鈥損erphenazine (PEI-P) conjugate which has a dual 鈥渁cceleration鈥搃nhibition鈥?modulation effect on amyloid 尾 (A尾) aggregation. Dose dependent results from Thioflavin T fluorescence assays, circular dichroism, and atomic force microscopy show that PEI-P conjugates accelerate formation of A尾 prefibrillar intermediates and then inhibit A尾 fibrillation. Furthermore, compared to perphenazine alone, PEI-P conjugates exhibit an enhanced inhibitory effect due to multivalency. Cell viability assays indicate that the PEI-P conjugates reduce the cytotoxicity of A尾 aggregates in a dose-dependent manner. This new modulation strategy may shed light on controlling amyloid aggregation, which offers a general concept for designing new modulators.