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

• 来源期刊: 药学学报（英文版）
• 关键词: Ricin toxin Ribosome-inactivating proteins Retrograde transport Post-exposure antidote Ricin antibody
• 年，卷（期）: 2020,（3）
• 页码范围: 498-511
• 页数: 14页
• 语种: 英文

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-2cycl,a series of novel compounds were obtained.The primary screen revealed that compound 27 has an improved anti-ricin 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 ECs0 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 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 in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.