Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication.
10.1016/j.apsb.2019.08.005
- Author:
Xu ZHAO
1
;
Haixia LI
2
;
Jia LI
1
;
Kunlu LIU
2
;
Bo WANG
2
;
Yuxia WANG
2
;
Xingzhou LI
1
;
Wu ZHONG
1
Author Information
1. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
- Publication Type:Journal Article
- Keywords:
Post-exposure antidote;
Retrograde transport;
Ribosome-inactivating proteins;
Ricin antibody;
Ricin toxin
- From:
Acta Pharmaceutica Sinica B
2020;10(3):498-511
- CountryChina
- Language:English
-
Abstract:
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-2, a series of novel compounds were obtained. The primary screen revealed that compound has an improved anti-ricin activity compare to positive control. pre-exposure evaluation in Madin-Darby Canine Kidney (MDCK) cells demonstrated that is a powerful anti-ricin compound with an EC of 41.05 nmol/L against one LC (lethal concentration, 5.56 ng/mL) of ricin. Further studies surprisingly indicated that confers post-exposure activity against ricin intoxication. An study showed that 1 h post-exposure administration of can improve the survival rate as well as delay the death of ricin-intoxicated mice. A drug combination of with monoclonal antibody mAb4C13 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 and post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.
