Bhatia Shiveena, Singh Manjinder, Singh Tanveer, Singh Varinder
Chitkara College of Pharmacy, Chitkara University, Punjab, India.
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A &M University Health Science Centre, Bryan, TX, 77807, USA.
Neurochem Res. 2023 Jan;48(1):13-25. doi: 10.1007/s11064-022-03722-w. Epub 2022 Aug 20.
Finding an effective cure for Alzheimer's disease has eluded scientists despite intense research. The disease is a cause of suffering for millions of people worldwide and is characterized by dementia accompanied by cognitive and motor deficits, ultimately culminating in the death of the patient. The course of the disease progression has various underlying contributing pathways, with the first and foremost factor being the development and accumulation of aberrant and misfolded proteins exhibiting neurotoxic functions. The impairment of cellular clearance mechanisms adds to their accumulation, resulting in neuronal death. This is where the PROteolysis TArgeting Chimera (PROTAC) technology comes into play, bringing the UPS degradation machinery in the proximity of the target protein for initiating its degradation and clearing abnormal protein debris with unparalleled precision demonstrating an edge over traditional protein inhibitors in many respects. The technology is widely explored in cancer research and utilized in the treatment of various tumors and malignancies, and is now being applied in treating AD. This review explores the application of PROTAC technology in developing lead compounds for managing this deadly disease along with detailing the pieces of evidence justifying its utility and efficacy.
尽管进行了深入研究，但科学家们仍未找到治疗阿尔茨海默病的有效方法。这种疾病给全球数百万人带来痛苦，其特征是痴呆症伴有认知和运动功能缺陷，最终导致患者死亡。疾病进展过程有多种潜在的促成途径，首要因素是具有神经毒性功能的异常和错误折叠蛋白质的产生和积累。细胞清除机制的损害加剧了它们的积累，导致神经元死亡。这就是蛋白酶靶向嵌合体（PROTAC）技术发挥作用的地方，它将泛素-蛋白酶体系统（UPS）降解机制带到靶蛋白附近，以启动其降解，并以前所未有的精度清除异常蛋白质碎片，在许多方面显示出优于传统蛋白质抑制剂的优势。该技术在癌症研究中得到广泛探索，并用于治疗各种肿瘤和恶性肿瘤，目前正应用于治疗阿尔茨海默病。这篇综述探讨了PROTAC技术在开发治疗这种致命疾病的先导化合物中的应用，并详细阐述了证明其效用和疗效的证据。
