School of Pharmacy, China Pharmaceutical University, Nanjing, China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Med Res Rev. 2021 Mar;41(2):858-901. doi: 10.1002/med.21745. Epub 2020 Oct 25.
Structural information of butyrylcholinesterase (BChE) and its variants associated with several diseases are discussed here. Pure human BChE has been proved safe and effective in treating organophosphorus (OPs) poisoning and has completed Phase 1 and 2 pharmacokinetic (PK) and safety studies. The introduction of specific mutations into native BChE to endow it a self-reactivating property has gained much progress in producing effective OPs hydrolases. The hydrolysis ability of native BChE on cocaine has been confirmed but was blocked to clinical application due to poor PK properties. Several BChE mutants with elevated cocaine hydrolysis activity were published, some of which have shown safety and efficiency in treating cocaine addiction of human. The increased level of BChE in progressed Alzheimer's disease patients made it a promising target to elevate acetylcholine level and attenuate cognitive status. A variety of selective BChE inhibitors with high inhibitory activity published in recent years are reviewed here. BChE could influence the weight and insulin secretion and resistance of BChE knockout (KO) mice through hydrolyzing ghrelin. The BChE-ghrelin pathway could also regulate aggressive behaviors of BChE-KO mice.
本文讨论了与多种疾病相关的丁酰胆碱酯酶（BChE）及其变体的结构信息。纯人源 BChE 已被证明在治疗有机磷（OPs）中毒方面是安全有效的，并已完成了 1 期和 2 期药代动力学（PK）和安全性研究。通过向天然 BChE 中引入特定突变使其具有自激活特性，在生产有效的 OPs 水解酶方面取得了很大进展。天然 BChE 对可卡因的水解能力已得到证实，但由于 PK 性质不佳，其临床应用受到阻碍。已发表了几种具有提高可卡因水解活性的 BChE 突变体，其中一些已显示出对人类可卡因成瘾治疗的安全性和有效性。进展性阿尔茨海默病患者的 BChE 水平升高，使其成为提高乙酰胆碱水平和减轻认知状态的有前途的靶点。本文综述了近年来发表的具有高抑制活性的多种选择性 BChE 抑制剂。BChE 通过水解脑肠肽影响 BChE 敲除（KO）小鼠的体重、胰岛素分泌和胰岛素抵抗。BChE-KO 小鼠的攻击行为也受 BChE-脑肠肽途径调节。
