酶抑制剂及其构效优化在阿尔茨海默病中的应用  

Application Study of Enzyme Inhibitors and Their Conformational Optimization in The Treatment of Alzheimer’s Disease

作　　者：储超扬 肖彪 单江晖 陈是燏 张楚霞 周钰愉 方甜园 林志成 谢凯 徐淑君[1] 李丽萍 CHU Chao-Yang;XIAO Biao;SHAN Jiang-Hui;CHEN Shi-Yu;ZHANG Chu-Xia;ZHOU Yu-Yu;FANG Tian-Yuan;LIN Zhi-Cheng;XIE Kai;XU Shu-Jun;LI Li-Ping(Department of Physiology and Pharmacology,Health Science Centre,Ningbo University,Ningbo 315211,China;Rehabilitative Department,the First Affiliated Hospital of Ningbo University,Ningbo 315211,China)

机构地区：[1]宁波大学医学部生理与病理学科,宁波315211 [2]宁波大学附属第一医院康复科,宁波315211

出　　处：《生物化学与生物物理进展》2024年第7期1510-1529,共20页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(82001155);浙江省自然科学基金(Y23H090031);浙江省省属高校基本科研业务费专项资金(SJLY2023008);宁波市自然科学基金(2023J068);浙江省医药卫生科技计划(2022KY1144);浙江省中医药科技计划(2023ZL162);宁波市重点研发计划(2023Z173);宁波市教育规划课题(2023YGH003);宁波大学教研项目(JYXMXZD2023030);宁波大学“大学生科技创新计划”(2023SRIP1919,2023SRIP1938);宁波大学海洋生物医药学科创新引智基地(D16013)资助;浙江省大学生科技创新活动计划(新苗人才计划)(2022R405A045)。

摘　　要：阿尔茨海默病(Alzheimer’s disease,AD)是一种以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性病变,而临床上缺乏有效治疗AD的药物。近些年来研究发现,多种酶抑制剂如胆碱酯酶抑制剂、单胺氧化酶抑制剂、分泌酶抑制剂等能改善胆碱能系统的障碍、Aβ的产生和沉积、Tau蛋白的过度磷酸化、氧化应激损伤、突触可塑性下降等AD发生发展的不同环节,从而改善AD症状和认知功能。本文综述了近年来酶抑制剂或抑制剂构效优化靶向调节胆碱酯酶、单胺氧化酶、分泌酶等在AD治疗中的研究进展,以期为AD的治疗和药物研发提供新思路。Alzheimer’s disease(AD)is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment,and there is a lack of effective drugs to treat AD clinically.Existing medications for the treatment of AD,such as Tacrine,Donepezil,Rivastigmine,and Aducanumab,only serve to delay symptoms and but not cure disease.To add insult to injury,these medications are associated with very serious adverse effects.Therefore,it is urgent to explore effective therapeutic drugs for AD.Recently,studies have shown that a variety of enzyme inhibitors,such as cholinesterase inhibitors,monoamine oxidase(MAO)inhibitors,secretase inhibitors,can ameliorate cholinergic system dysfunction,Aβproduction and deposition,Tau protein hyperphosphorylation,oxidative stress damage,and the decline of synaptic plasticity,thereby improving AD symptoms and cognitive function.Some plant extracts from natural sources,such as Umbelliferone,Aaptamine,Medha Plus,have the ability to inhibit cholinesterase activity and act to improve learning and cognition.Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site(CAS)and peripheral anionic site(PAS)sites of acetylcholinesterase(AChE),which can inhibit AChE activity and ameliorate cholinergic system disorders.A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase,increase monoamine levels in the brain,and reduce Aβdeposition.Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage.Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβburden and promote learning and memory of mice.The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase,and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase.A series of hybrids,obtained by an amide linker of chromone in comb

关 键 词：阿尔茨海默病 乙酰胆碱酯酶抑制剂 单胺氧化酶抑制剂 β分泌酶抑制剂 γ分泌酶抑制剂 糖原合成酶激酶抑制剂 抑制剂构效优化 

分 类 号：R74[医药卫生—神经病学与精神病学]