Positively Charged Chitosan and N-Trimethyl Chitosan Inhibit A尾40 Fibrillogenesis
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- 作者：Haiyang Liu ; Bimlesh Ojha ; Clifford Morris ; Mengting Jiang ; Ewa P. Wojcikiewicz ; Praveen P. N. Rao ; Deguo Du
- 刊名：Biomacromolecules
- 出版年：2015
- 出版时间：August 10, 2015
- 年：2015
- 卷：16
- 期：8
- 页码：2363-2373
- 全文大小：653K
- ISSN：1526-4602
文摘
Amyloid fibrils, formed by aggregation of improperly folded or intrinsically disordered proteins, are closely related with the pathology of a wide range of neurodegenerative diseases. Hence, there is a great deal of interest in developing molecules that can bind and inhibit amyloid formation. In this regard, we have investigated the effect of two positively charged polysaccharides, chitosan (CHT) and its quarternary derivative N-trimethyl chitosan chloride (TMC), on the aggregation of A尾40 peptide. Our aggregation kinetics and atomic force microscopy (AFM) studies show that both CHT and TMC exhibit a concentration-dependent inhibiting activity on A尾40 fibrillogenesis. Systematic pH-dependent studies demonstrate that the attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues in A尾40 play a key role in this inhibiting activity. The stronger inhibiting activity of TMC than CHT further suggests the importance of charge density of the polymer chain in interacting with A尾40 and blocking the fibril formation. The possible interactions between CHT/TMC and A尾40 are also revealed at the atomic level by molecular docking simulation, showing that the A尾40 monomer could be primarily stabilized by electrostatic interactions with charged amines of CHT and quaternary amines of TMC, respectively. Binding of CHT/TMC on the central hydrophobic core region of A尾40 peptide may be responsible for blocking the propagation of the nucleus to form fibrillar structures. These results suggest that incorporation of sugar units such as d-glucosamine and N-trimethyl-d-glucosamine into polymer structural template may serve as a new strategy for designing novel antiamyloid molecules.