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

Journal: Acta pharmaceutica Sinica. B
Published Date: Aug 22, 2019

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.

Authors

  • Xu Zhao
    Intensive Care Unit, Hubei University of Medicine, Renmin Hospital, Shiyan, Hubei, China.
  • Haixia Li
    State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • Jia Li
    Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • Kunlu Liu
    State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • Bo Wang
    Department of Clinical Laboratory Medicine Center, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia, China.
  • Yuxia Wang
    Department of Reproductive Medicine, The First Affiliated Hospital, Jinan University Guangzhou 510000, Guangdong, China.
  • Xingzhou Li
    National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • Wu Zhong
    National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

Keywords

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