Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication
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...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Book |
| Published: |
Elsevier,
2020-03-01T00:00:00Z.
|
| Subjects: | |
| Online Access: | Connect to this object online. |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
MARC
| LEADER | 00000 am a22000003u 4500 | ||
|---|---|---|---|
| 001 | doaj_7902cb48a21d44c28baffc476efc94e9 | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Xu Zhao |e author |
| 700 | 1 | 0 | |a Haixia Li |e author |
| 700 | 1 | 0 | |a Jia Li |e author |
| 700 | 1 | 0 | |a Kunlu Liu |e author |
| 700 | 1 | 0 | |a Bo Wang |e author |
| 700 | 1 | 0 | |a Yuxia Wang |e author |
| 700 | 1 | 0 | |a Xingzhou Li |e author |
| 700 | 1 | 0 | |a Wu Zhong |e author |
| 245 | 0 | 0 | |a Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication |
| 260 | |b Elsevier, |c 2020-03-01T00:00:00Z. | ||
| 500 | |a 2211-3835 | ||
| 500 | |a 10.1016/j.apsb.2019.08.005 | ||
| 520 | |a 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 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 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. Key words: Ricin toxin, Ribosome-inactivating proteins, Retrograde transport, Post-exposure antidote, Ricin antibody | ||
| 546 | |a EN | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Acta Pharmaceutica Sinica B, Vol 10, Iss 3, Pp 498-511 (2020) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2211383519306185 | |
| 787 | 0 | |n https://doaj.org/toc/2211-3835 | |
| 856 | 4 | 1 | |u https://doaj.org/article/7902cb48a21d44c28baffc476efc94e9 |z Connect to this object online. |