托卡朋衍生物PCDNA抑制Aβ42纤维化并降低其细胞毒性

Tolcapone derivative PCDNA inhibits Aβ42 fibrillogenesis and reduces its cytotoxicity

淀粉样β蛋白(amyloid-βprotein,Aβ)在脑内的异常聚集是诱发阿尔茨海默症(Alzheimer’s disease,AD)的重要原因,因此开发抑制Aβ聚集的药物是治疗AD的重要手段之一。前期研究发现托卡朋能抑制Aβ42聚集并降低Aβ42聚集物诱导的细胞毒性,但临床研究发现托卡朋有很强的肝毒性。为了降低托卡朋的肝毒性,对其侧链结构进行改造并获得其衍生物苯乙基(E)-2-氰基-3-(3,4二羟基-5-硝基苯)-丙烯酸酯(PCDNA)。通过硫磺素T(thioflavin T,ThT)和原子力显微镜(atomic force microscopy,AFM)实验研究了PCDNA对Aβ42纤维化的抑制作用;通过细胞毒性实验研究了PCDNA对Aβ42聚集物诱导的细胞毒性作用;并研究了PCDNA对成熟Aβ42纤维的解聚作用。最后,通过分子对接实验研究了PCDNA与Aβ42五聚体之间的相互作用。这些实验结果为研究托卡朋结构类似物作为Aβ抑制剂奠定了基础。

Abnormal aggregation of amyloid-βprotein(Aβ)in brain plays a vital role in the occurrence of Alzheimer’s disease(AD).Hence,inhibiting Aβaggregation is one major tactic for therapy of AD.Previous studies have found that tolcapone can inhibit Aβ42 aggregation and reduce the cytotoxicity induced by Aβ42 aggregates,but clinical studies have found that tolcapone has strong liver toxicity.To reduce the liver toxicity of tolcapone,its side chain structure was modified to obtain its derivative phenethyl(E)-2-cyano-3-(3,4 dihydroxy-5-nitrobenzene)-acrylate(PCDNA).Thioflavin T(ThT)and atomic force microscopy(AFM)assays were used to explore the inhibitory effect of PCDNA on Aβ42 fibrillogenesis.The cytotoxicity assays were used to explore the inhibitory effect of PCDNA against the cytotoxicity induced by Aβ42 aggregates.In addition,the depolymerization effect of PCDNA on mature Aβ42 fibrils was also explored.Finally,molecular docking was used to explore the interaction between PCDNA and Aβ42 pentamer.These results lay the foundation for the study of the structural analogues of tolcapone as Aβinhibitors.