Centro de Biología Celular y Molecular de Enfermedades , Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge Edif #208 , Panama 0843-01103 , Panama.
Department of Biotechnology , Acharya Nagarjuna University , Nagarjuna Nagar , Guntur , Andhra Pradesh 522510 , India.
ACS Chem Neurosci. 2019 Oct 16;10(10):4250-4263. doi: 10.1021/acschemneuro.9b00297. Epub 2019 Oct 7.
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 Aβ, 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 Aβ and/or disaggregate the fibril. Docking experiments suggest that the nonpolar component of the interaction of compounds with Aβ contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds via interaction with hydrophobic moieties of the fibril. Consistently, compounds and were able to mitigate Aβ fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aβ aggregates and the paralysis associated with Aβ toxicity in . Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.
阿尔茨海默病（AD）是老年人中最常见的痴呆症形式，已成为全球主要的公共卫生关注问题。它给护理人员和家庭带来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肽的聚集物组成，主要是由淀粉样前体蛋白（APP）切割产生的 Aβ。Aβ是治疗 AD 的重要靶点，但迄今为止，尚未发现有效的 Aβ清除治疗方法。我们已经确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 Aβ的聚集和/或解聚纤维。对接实验表明，化合物与 Aβ相互作用的非极性部分有利于每个复合物的结合自由能。分子动力学模拟表明，化合物通过与纤维的疏水性部分相互作用具有纤维解聚活性。一致地，化合物 和 能够减轻 Aβ纤维诱导的大鼠嗜铬细胞瘤细胞（PC12）死亡。其中一种化合物减少了 Aβ聚集的形成 以及 Aβ毒性相关的麻痹 。因此，我们的研究增强了识别和表征可能有助于阻止或延缓 AD 进展的新药物的努力。
