Hexahydropyrrolo[2,3-b]indole Compounds as Potential Therapeutics for Alzheimer's Disease.
Hexahydropyrrolo[2,3-b]indole Compounds as Potential Therapeutics for Alzheimer's Disease.
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DOI：
10.1021/acschemneuro.9b00297
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发表时间：
2019-10-16
影响因子：
5
通讯作者：
Fernández PL
中科院分区：
文献类型：
--
作者：
Doens D;Valdés-Tresanco ME;Vasquez V;Carreira MB;De La Guardia Y;Stephens DE;Nguyen VD;Nguyen VT;Gu J;Hegde ML;Larionov OV;Valiente PA;Lleonart R;Fernández PL
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，并且已经成为全球主要的公共卫生问题。这对照顾者和家庭造成了巨大的经济和心理负担。细胞外淀粉样蛋白β（Aβ）斑块的存在是这种神经退行性疾病的标志之一。淀粉样斑块由Aβ肽（主要是Aβ42）的聚集体组成，其来源于淀粉样前体蛋白（APP）的裂解。Aβ 42是治疗AD的重要靶点，但迄今为止，还没有发现有效的清除Aβ 42的药物，我们已经鉴定了四种新的六氢吡咯并吲哚（HPI）合成化合物，它们能够抑制Aβ42的聚集和/或解聚原纤维。对接实验表明，化合物与Aβ42相互作用的非极性组分有利于每个复合物的结合自由能。分子动力学模拟表明化合物1通过与原纤维的疏水部分相互作用而具有原纤维解聚活性。结果表明，化合物1和2能减轻Aβ42纤维诱导的大鼠嗜铬细胞瘤细胞（PC 12）死亡。其中一种化合物可减少体内Aβ聚集体的形成以及秀丽隐杆线虫中与Aβ毒性相关的麻痹。因此，我们的研究增加了可能有助于阻止或延缓AD进展的新药物的鉴定和表征的努力。
Alzheimer’s disease (AD) is the most common form of dementia among the elderly and has become a leading public health concern worldwide. It represents a huge economic and psychological burden to caregivers and families. The presence of extracellular amyloid beta (Aβ) plaques is one of the hallmarks of this neurodegenerative disorder. Amyloid plaques are comprised of aggregates of Aβ peptides, mainly Aβ42, originated by the cleavage of the amyloid precursor protein (APP). Aβ is a crucial target for the treatment of AD, but to date, no effective treatment for the clearance of Aβ has been found. We have identified four new hexahydropyrroloindoles (HPI) synthetic compounds that are able to inhibit the aggregation of Aβ42 and/or disaggregate the fibril. Docking experiments suggest that the non-polar component of the interaction of compounds with Aβ42 contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds 1 via interaction with hydrophobic moieties of the fibril. Consistently, compounds 1 and 2 were able to mitigate Aβ42 fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aβ aggregates in vivo and the paralysis associated with Aβ toxicity in Caenorhabditis elegans. Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.
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DOI：
10.1073/pnas.1121005109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Bulawa, Christine E.;Connelly, Stephen;Labaudiniere, Richard
通讯作者：
Labaudiniere, Richard
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
影响因子：
4.6
作者：
Evangelisti E;Cascella R;Becatti M;Marrazza G;Dobson CM;Chiti F;Stefani M;Cecchi C
通讯作者：
Cecchi C
影响因子：
2.7
作者：
Coelho-Cerqueira, Eduardo;Pinheiro, Anderson S.;Follmer, Cristian
通讯作者：
Follmer, Cristian