纤维
低聚物
生物物理学
化学
肽
合理设计
淀粉样蛋白(真菌学)
莫西沙星
蛋白质聚集
硫黄素
生物化学
阿尔茨海默病
抗生素
生物
疾病
纳米技术
医学
材料科学
内科学
无机化学
有机化学
作者
Asra Nasir Khan,Faisal Nabi,Mohammad Ajmal,Syed Moasfar Ali,Fahad M. Almutairi,Adel I. Alalawy,Rizwan Hasan Khan
标识
DOI:10.1021/acschemneuro.2c00371
摘要
The aggregation of Aβ42 is established as a key factor in the development of Alzheimer's disease (AD). Consequently, molecules that inhibit aggregation of peptide may lead to therapies to prevent or control AD. Several studies suggest that oligomeric intermediates present during aggregation may be more cytotoxic than fibrils themselves. In this work, we examine the inhibitory activity of an antibiotic MXF on aggregation (fibrils and oligomers) and disaggregation of Aβ42 using various biophysical and microscopic studies. Computational analysis was done to offer mechanistic insight. The amyloid formation of Aβ42 is suppressed by MXF, as demonstrated by the decrease in both the corresponding ThT fluorescence intensity and other biophysical techniques. The lag phase of amyloid formation doubled from 4.53 to 9.66 h in the presence of MXF. The addition of MXF at the completion of the fibrillation reaction, as monitored by ThT, led to a rapid, concentration dependent, exponential decrease in fluorescence signal that was consistent with loss of fibrils. We used TEM to directly demonstrate that MXF caused fibrils to disassemble. Our docking results show that MXF binds to both monomeric and fibrillar forms of Aβ42 with significant affinities. We also observed breaking of fibrils in the presence of MXF through molecular dynamics simulation. These findings suggest that antibiotic MXF could be a promising lead compound with dual role as fibril/oligomer inhibitor and disaggregase for further development as potential repurposed therapeutic against AD.
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