Bioorganic Chemistry Laboratory, New Chemistry Unit , Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur P.O., Bengaluru , 560064 Karnataka , India.
ACS Chem Neurosci. 2019 Aug 21;10(8):3611-3621. doi: 10.1021/acschemneuro.9b00216. Epub 2019 Jun 12.
Alzheimer's disease (AD) is one of the most devastating forms of dementia, without reliable treatments to cure, delay the onset, or prevent the disease progression. The proposed toxic mechanisms of AD include amyloidogenesis of amyloid β (Aβ), metal ion dyshomeostasis, redox active metal-Aβ inclusion complex formation, and generation of excessive reactive oxygen and nitrogen species (ROS and RNS). The imbalance in redox homeostasis causes oxidative stress, DNA damage, mitochondrial dysfunction, and inflammation, which collectively become a major hurdle in the development of effective therapeutic agents for multifactorial AD. This necessitates a multifunctional strategy to develop effective therapeutic agents to inhibit multifaceted toxicity. In this context, we report a rational design, synthesis, and detailed study to identify a small molecule multifunctional modulator (MFM) inspired by the human origin tripeptide. The lead, MFM , chelates and sequesters metal ions, disrupts their redox cycles, prevents excessive ROS production and oxidative stress, ameliorates oxidative DNA damage and mitochondrial dysfunction, and modulates Nrf2 protein signaling under oxidative stress conditions by eliminating the toxic stress elements. The MFM was found to inhibit metal-dependent and -independent Aβ aggregation and qualified as a suitable candidate to inhibit Aβ-induced neuronal toxicity. The NMR spectroscopy study revealed molecular-level interactions of with Aβ42, which explain the mechanism of aggregation inhibition. Furthermore, effectively inhibited inflammation as revealed by reduction in nitric oxide (NO) production in LPS-activated glial cells. These key features make a potential MFM platform to develop therapeutic agents for metal (Cu, Zn and Fe)-dependent and -independent multifaceted Aβ toxicity of AD.
阿尔茨海默病（AD）是最具破坏性的痴呆症形式之一，目前尚无可靠的治疗方法来治愈、延缓发病或阻止疾病进展。AD 的拟议毒性机制包括淀粉样蛋白β（Aβ）的淀粉样形成、金属离子动态平衡失调、氧化还原活性金属-Aβ包含复合物的形成以及过量活性氧和氮物种（ROS 和 RNS）的产生。氧化还原平衡的失衡会导致氧化应激、DNA 损伤、线粒体功能障碍和炎症，这些共同成为开发针对多因素 AD 的有效治疗药物的主要障碍。这需要一种多功能策略来开发有效的治疗药物，以抑制多方面的毒性。在这种情况下，我们报告了一个合理的设计、合成和详细研究，以确定一种受人类三肽启发的小分子多功能调节剂（MFM）。该先导化合物 MFM 螯合和隔离金属离子，破坏其氧化还原循环，防止过量 ROS 产生和氧化应激，改善氧化 DNA 损伤和线粒体功能障碍，并在氧化应激条件下通过消除有毒应激元素来调节 Nrf2 蛋白信号。发现 MFM 抑制金属依赖性和非依赖性 Aβ 聚集，并被证明是抑制 Aβ 诱导的神经元毒性的合适候选物。NMR 光谱研究揭示了 与 Aβ42 的分子水平相互作用，这解释了抑制聚集的机制。此外， 有效抑制了由 LPS 激活的神经胶质细胞中一氧化氮（NO）产生减少所揭示的炎症。这些关键特征使 成为一种有潜力的 MFM 平台，可用于开发针对 AD 中金属（Cu、Zn 和 Fe）依赖性和非依赖性多方面 Aβ 毒性的治疗药物。
