Fan Yujuan, Wu Daohong, Yi Xinyao, Tang Hailin, Wu Ling, Xia Yonghong, Wang Zixiao, Liu Qiuhua, Zhou Zaichun, Wang Jianxiu
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, Hunan, P. R. China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong, P. R. China.
ACS Omega. 2017 Aug 31;2(8):4188-4195. doi: 10.1021/acsomega.7b00877. Epub 2017 Aug 3.
The aggregation or misfolding of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Aβ aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Aβ aggregation and to lower Aβ-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Aβ aggregation but also disassemble the preformed Aβ aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and Aβ at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 μM, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the Aβ aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy.
淀粉样β蛋白（Aβ）的聚集或错误折叠是阿尔茨海默病（AD）的主要病理标志。Aβ聚集的调控被认为是治疗AD的有效策略。研究证实了水溶性卟啉5,10,15,20-四（-甲基-4-吡啶基）卟啉（TMPyP）具有抑制Aβ聚集及降低Aβ诱导毒性的能力。表面等离子体共振和圆二色性结果表明，TMPyP不仅能破坏Aβ聚集，还能拆解预先形成的Aβ聚集体。原子力显微镜成像证明TMPyP可抑制寡聚体和原纤维的形成。分子动力学模拟从分子水平深入了解了TMPyP与Aβ之间的相互作用。TMPyP作用于寡聚体和原纤维的半数抑制浓度分别测定为0.6和0.43μM。作为卟啉家族的一员，TMPyP具有相当低的细胞毒性，与TMPyP共同孵育后，Aβ聚集体的细胞毒性也有所减轻。TMPyP的优异性能使其成为AD治疗的潜在候选药物。
