托卡朋衍生物PCDNA抑制Aβ42纤维化并降低其细胞毒性

被引：2

作者：

陈贝贝 ^{[1
]}

蒋露莹 ^{[1
]}

郭芳妍 ^{[2
]}

屈莉莉 ^{[1
]}

汪文倩 ^{[1
]}

金成华 ^{[2
]}

刘夫锋 ^{[1
]}

机构：

[1] 天津科技大学生物工程学院

[2] 延边大学药学院

来源：

药学学报 | 2021年 / 56卷 / 04期

基金：

天津市自然科学基金;

关键词：

阿尔茨海默症; 淀粉样β蛋白; 抑制剂; 托卡朋衍生物; 纤维化; 分子对接;

D O I：

10.16438/j.0513-4870.2020-1853

中图分类号：

R965 [实验药理学];

学科分类号：

100602 ; 100706 ;

摘要：

淀粉样β蛋白(amyloid-β protein, 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。

引用

页码：1063 / 1069

页数：7

共 32 条

[1] Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease [J].

Mo, Jun ;

Chen, Tingkai ;

Yang, Hongyu ;

Guo, Yan ;

Li, Qi ;

Qiao, Yuting ;

Lin, Hongzhi ;

Feng, Feng ;

Liu, Wenyuan ;

Chen, Yao ;

Liu, Zongliang ;

Sun, Haopeng .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2020, 35 (01) :330-343

[2] Distinguishing the Effect on the Rate and Yield of Aβ42 Aggregation by Green Tea Polyphenol EGCG [J].

Park, Giovanna ;

Xue, Christine ;

Wang, Hongsu ;

Guo, Zhefeng .

ACS OMEGA, 2020, 5 (34) :21497-21505

[3]

Human islet amyloid polypeptide (hIAPP) - a curse in type II diabetes mellitus: insights from structure and toxicity studies..[J].Bishoyi Ajit Kumar;Roham Pratiksha H;Rachineni Kavitha;Save Shreyada;Hazari M Asrafuddoza;Sharma Shilpy;Kumar Ashutosh.Biological chemistry.2020, 2

[4] α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis [J].

Mehra, Surabhi ;

Sahay, Shruti ;

Maji, Samir K. .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2019, 1867 (10) :890-908

[5] Amyloid-β Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity [J].

Honcharenko, Dmytro ;

Juneja, Alok ;

Roshan, Firoz ;

Maity, Jyotirmoy ;

Galan-Acosta, Lorena ;

Biverstal, Henrik ;

Hjorth, Erik ;

Johansson, Jan ;

Fisahn, Andre ;

Nilsson, Lennart ;

Stromberg, Roger .

ACS CHEMICAL NEUROSCIENCE, 2019, 10 (03) :1462-1477

[6]

Pharmacodynamic evaluation of novel Catechol- O -methyltransferase inhibitors.[J].Sofia Dimitri Pinheiro;Maria Paula Serrão;Tiago Silva;Fernanda Borges;Patrício Soares-da-Silva.European Journal of Pharmacology.2019,

[7] Hydroxylated Single-Walled Carbon Nanotubes Inhibit Aβ42 Fibrillogenesis, Disaggregate Mature Fibrils, and Protect against Aβ42-Induced Cytotoxicity [J].

Liu, Fufeng ;

Wang, Wenjuan ;

Sang, Jingcheng ;

Jia, Longgang ;

Lu, Fuping .

ACS CHEMICAL NEUROSCIENCE, 2019, 10 (01) :588-598

[8] Amyloid assembly and disassembly [J].

Chuang, Edward ;

Hori, Acacia M. ;

Hesketh, Christina D. ;

Shorter, James .

JOURNAL OF CELL SCIENCE, 2018, 131 (08)

[9]

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease.[J].C. Cheignon;M. Tomas;D. Bonnefont-Rousselot;P. Faller;C. Hureau;F. Collin.Redox Biology.2018,

[10] Serum Albumin's Protective Inhibition of Amyloid-β Fiber Formation Is Suppressed by Cholesterol, Fatty Acids and Warfarin [J].

Bode, David C. ;

Stanyon, Helen F. ;

Hirani, Trisha ;

Baker, Mark D. ;

Nield, Jon ;

Viles, John H. .

JOURNAL OF MOLECULAR BIOLOGY, 2018, 430 (07) :919-934

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