Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication

作     者：Xu Zhao Haixia Li Jia Li Kunlu Liu Bo Wang Yuxia Wang Xingzhou Li Wu Zhong Xu Zhao;Haixia Li;Jia Li;Kunlu Liu;Bo Wang;Yuxia Wang;Xingzhou Li;Wu Zhong

作者机构：National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing 100850China State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Institute of Pharmacology and ToxicologyBeijing 100850China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第3期

页      面：498-511页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 100602[医学-中西医结合临床] 

基　　金：the financial supports of the National Science and Technology Major Projects for"Major New Drugs Innovation and Development"(2018ZX09711003-001-001)of China. 

主　　题：Ricin toxin Ribosome-inactivating proteins Retrograde transport Post-exposure antidote Ricin antibody 

摘      要：Ricin is a highly toxic type 2 ribosome-inactivating protein(RIP)which is extracted from the seeds of castor beans.Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far.In this study,by structural modification of a retrograde transport blocker Retro-2cyc1,a series of novel compounds were obtained.The primary screen revealed that compound 27 has an improved antiricin activity compare to positive control.In vitro pre-exposure evaluation in Madin-Darby Canine Kidney(MDCK)cells demonstrated that 27 is a powerful anti-ricin compound with an EC50 of 41.05 nmol/L against one LC(lethal concentration,5.56 ng/mL)of ricin.Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication.An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice.A drug combination of 27 with monoclonal antibody mAb4 C13 rescued mice from one LD(lethal dose)ricin challenge and the survival rate of tested animals is 100%.These results represent,for the first time,indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.