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

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 combine with the benzylpiperidine moieties of donepezil,have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity.Single domain antibodies(such as AAV-VHH)targeted the inhibition of BACE1 can reduce Aβproduction and deposition as well as the levels of inflammatory cells,which ultimately improve synaptic plasticity.3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity ofγ-secretase,thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice.Inhibitingγ-secretase activity which leads to the decline of inflammatory factors(such as IFN-γ,IL-8)not only directly improves the pathology of AD,but also reduces Aβproduction.Melatonin reduces the transcriptional expression of GSK-3βmRNA,thereby decreasing the levels of GSK-3βand reducing the phosphorylation induced by GSK-3β.Hydrogen sulfide can inhibit GSK-3βactivity via sulfhydration of the Cys218 site of GSK-3β,resulting in the suppression of Tau protein hyperphosphorylation,which ameliorate the motor deficits and cognitive impairment in mice with AD.This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase,monoamine oxidase,secretase,and GSK-3β.We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors,which may be useful in treating AD.