Bacterial 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.
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