Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01
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- 作者：Sharmistha Sinha ; Zhenming Du ; Panchanan Maiti ; Frank-Gerrit Kl盲rner ; Thomas Schrader ; Chunyu Wang ; Gal Bitan
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：June 20, 2012
- 年：2012
- 卷：3
- 期：6
- 页码：451-458
- 全文大小：373K
- 年卷期：v.3,no.6(June 20, 2012)
- ISSN：1948-7193
文摘
Many compounds have been tested as inhibitors or modulators of amyloid 尾-protein (A尾) assembly in hope that they would lead to effective, disease-modifying therapy for Alzheimer鈥檚 disease (AD). These compounds typically were either designed to break apart 尾-sheets or selected empirically. Two such compounds, the natural inositol derivative scyllo-inositol and the green-tea-derived flavonoid epigallocatechin gallate (EGCG), currently are in clinical trials. Similar to most of the compounds tested thus far, the mechanism of action of scyllo-inositol and EGCG is not understood. Recently, we discovered a novel family of assembly modulators, Lys-specific molecular tweezers, which act by binding specifically to Lys residues and modulate the self-assembly of amyloid proteins, including A尾, into formation of nontoxic oligomers by a process-specific mechanism (Sinha, S., Lopes, D. H., Du, Z., Pang, E. S., Shanmugam, A., Lomakin, A., Talbiersky, P., Tennstaedt, A., McDaniel, K., Bakshi, R., Kuo, P. Y., Ehrmann, M., Benedek, G. B., Loo, J. A., Klarner, F. G., Schrader, T., Wang, C., and Bitan, G. (2011) Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. J. Am. Chem. Soc.133, 16958鈥?6969). Here, we compared side-by-side the capability of scyllo-inositol, EGCG, and the molecular tweezer CLR01 to inhibit A尾 aggregation and toxicity. We found that EGCG and CLR01 had comparable activity whereas scyllo-inositol was a weaker inhibitor. Exploration of the binding of EGCG and CLR01 to A尾 using heteronuclear solution-state NMR showed that whereas CLR01 bound to the two Lys and single Arg residues in A尾 monomers, only weak, nonspecific binding was detected for EGCG, leaving the binding mode of the latter unresolved.