کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2036895 | 1072289 | 2010 | 12 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge](/preview/png/2036895.png)
SummaryBacterial Shiga-like toxins are virulence factors that constitute a significant public health threat worldwide, and the plant toxin ricin is a potential bioterror weapon. To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus. Here, we used high-throughput screening to identify small molecule inhibitors that protect cells from ricin and Shiga-like toxins. We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity. In mice, one compound clearly protects from lethal nasal exposure to ricin. Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target.
Graphical AbstractFigure optionsDownload high-quality image (361 K)Download as PowerPoint slideHighlights
► Identification of two toxin inhibitors by cell-based high-throughput screening
► Cells are protected against the plant toxin ricin and bacterial Shiga-like toxins
► Inhibitors selectively block toxin trafficking at endosome-TGN interface
► One compound protects mice from lethal nasal challenge with ricin
Journal: - Volume 141, Issue 2, 16 April 2010, Pages 231–242