肉毒神经毒素小分子抑制剂的研究进展  

Research advances in small molecule inhibitors of botulinum neurotoxins

作　　者：田自有 陈赛贞 周金明[2] 梁斌 TIAN Zi-you;CHEN Sai-zhen;ZHOU Jin-ming;LINAG-Bin(Department of Pharmacy, Taizhou Institute Hospital, Taizhou Central Hospital, Taizhou 318000, China;Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China)

机构地区：[1]浙江省台州市中心医院台州学院附属医院药剂科,浙江台州318000 [2]中国医学科学院医药生物技术研究所,北京100050

出　　处：《中国药理学与毒理学杂志》2019年第3期232-240,共9页Chinese Journal of Pharmacology and Toxicology

基　　金：浙江省药学会医院药学专项科研资助项目(2018ZYY50)~~

摘　　要：肉毒神经毒素(BoNT)是目前已知毒性最大的生物毒素,分为血清型A^G,具有高专一性地使表面神经末梢迟缓性麻痹的特点。由于BoNT具有简单易得和特殊的作用机制,近年来被广泛应用于美容和临床治疗及研究,存在由于过量使用引起中毒的风险。同时,由于其高毒性,BoNT也是潜在的恐怖分子比较青睐的生化武器。因此,对于BoNT抑制剂的研究刻不容缓。本文综述了BoNT的结构及其引起中毒的分子机制,重点综述了近年来靶向A型BoNT轻链锌活性位点的8-羟基喹啉类、异羟肟羧酸类小分子抑制剂、A型BoNT轻链共价结合的不可逆小分子抑制剂、靶向A型BoNT轻链外结合位点的小分子非竞争抑制剂,以及靶向B、E型BoNT轻链的小分子抑制剂等方面的研究进展。Botulinum neurotoxins (BoNTs) are the most deadly biological substances, including seven BoNT serotypes (A-G), and characterized by persistent flaccid paralysis of peripheral never terminals with high specificity called botulism. Due to their easy production and well-defined biological mechanism, BoNTs are wildly used in cosmetics and as very particular biopharmaceuticals in clinical therapy, so there is the risk of poisoning caused by accidental overdose. Also, because of their high toxicity, they are potential bioterrorism weapons. Thus, there is an urgent need for the development of BoNT inhibitors. In this review, based on the structure of BoNTs and the mechanism of botulism, we summarize recent advances in small molecule inhibitors targeting the Zn2+ active site of BoNT/A, such as 8-hydroxyquinoline and hydroxamic acid, or exosite of BoNT/A, small molecule inhibitors of BoNT/A through covalent binding that are irreversible, as well as small molecule inhibitors of targeting BoNT/B/E light chain (LC).

关 键 词：肉毒神经毒素 肉毒神经毒素中毒 迟缓性麻痹 小分子抑制剂 

分 类 号：R966[医药卫生—药理学]