Sun_2024_Eur.J.Med.Chem_275_116569

Butyrylcholinesterase (BChE), also known as pseudocholinesterase and serum cholinesterase, is an isoenzyme of acetylcholinesterase (AChE). It mediates the degradation of acetylcholine, especially under pathological conditions. Proverbial pharmacological applications of BChE, its mutants and modulators consist of combating Alzheimer's disease (AD), influencing multiple sclerosis (MS), addressing cocaine addiction, detoxifying organophosphorus poisoning and reflecting the progression or prognosis of some diseases. Of interest, recent reports have shed light on the relationship between BChE and lipid metabolism. It has also been proved that BChE is going to increase abnormally as a compensator for AChE in the middle and late stages of AD, and BChE inhibitors can alleviate cognitive disorders and positively influence some pathological features in AD model animals, foreboding favorable prospects and potential applications. Herein, the selective BChE inhibitors and BChE-related multitarget-directed ligands published in the last three years were briefly summarized, along with the currently known pharmacological applications of BChE, aiming to grasp the latest research directions. Thereinto, some emerging strategies for designing BChE inhibitors are intriguing, and the modulators based on target combination of histone deacetylase and BChE against AD is unprecedented. Furthermore, the involvement of BChE in the hydrolysis of ghrelin, the inhibition of low-density lipoprotein (LDL) uptake, and the down-regulation of LDL receptor (LDLR) expression suggests its potential to influence lipid metabolism disorders. This compelling prospect likely stimulates further exploration in this promising research direction.