Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bengaluru, Karnataka 560064, India.
ACS Chem Neurosci. 2022 Jul 20;13(14):2209-2221. doi: 10.1021/acschemneuro.2c00276. Epub 2022 Jun 27.
Synergistic modulation of multifaceted toxicity is the key to tackle multifactorial Alzheimer's disease (AD). The etiology of AD includes amyloid β (Aβ) amyloidosis, metal ion dyshomeostasis, reactive oxygen species (ROS), oxidative stress, mitochondrial damage, and neuroinflammation. We rationally designed multifunctional modulators by integrating pharmacophores for metal chelation, antioxidant and anti-inflammatory properties, and modulation of Aβ42 aggregation on the naphthalene monoimide (NMI) scaffold. The in vitro and cellular studies of NMIs revealed that M3 synergistically modulates metal-independent and -dependent amyloid toxicity, scavenges ROS, alleviates oxidative stress, and emulates Nrf2-mediated stress response in neuronal cells. M3 effectively reduced structural and functional damage of mitochondria, reduced Cyt levels, and rescued cells from apoptosis. The biological atomic force microscopy and Western blot analysis revealed the ability of M3 to suppress microglial activation and neuroinflammation through inhibition of the NF-κβ pathway. The synergistic action of M3 is in agreement with our design strategy to develop a multifunctional therapeutic candidate by integrating multiple pharmacophores with distinct structural and functional elements to ameliorate the multifaceted toxicity of AD.
协同调节多方面的毒性是解决多因素阿尔茨海默病（AD）的关键。AD 的病因包括淀粉样蛋白 β（Aβ）淀粉样变性、金属离子动态平衡失调、活性氧（ROS）、氧化应激、线粒体损伤和神经炎症。我们通过整合用于金属螯合、抗氧化和抗炎特性以及调节 Aβ42 聚集的药效团，在萘单酰亚胺（NMI）支架上合理设计了多功能调节剂。NMIs 的体外和细胞研究表明，M3 协同调节金属非依赖性和依赖性淀粉样毒性，清除 ROS，减轻氧化应激，并在神经元细胞中模拟 Nrf2 介导的应激反应。M3 有效减少了线粒体的结构和功能损伤，降低 Cyt 水平，并使细胞免于凋亡。生物原子力显微镜和 Western blot 分析表明，M3 通过抑制 NF-κβ 通路抑制小胶质细胞激活和神经炎症的能力。M3 的协同作用符合我们的设计策略，即通过整合具有不同结构和功能元素的多个药效团来开发多功能治疗候选物，以改善 AD 的多方面毒性。
