Inhibition of retrograde transport protects mice from lethal ricin challenge.
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.
Stechmann
Bahne
B
Traffic, Signaling, and Delivery Laboratory, Centre de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Bai
Siau-Kun
SK
Gobbo
Emilie
E
Lopez
Roman
R
Merer
Goulven
G
Pinchard
Suzy
S
Panigai
Laetitia
L
Tenza
Danièle
D
Raposo
Graça
G
Beaumelle
Bruno
B
Sauvaire
Didier
D
Gillet
Daniel
D
Johannes
Ludger
L
Barbier
Julien
J
D000281:Administration, Intranasal; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D021381:Protein Transport; D050765:Qa-SNARE Proteins / Q000378:metabolism; D012276:Ricin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D022603:Shiga Toxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D021601:trans-Golgi Network / Q000378:metabolism
C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; C549072:7-bromo-5-phenyl-4-propionyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one; D001549:Benzamides; D001570:Benzodiazepinones; D050765:Qa-SNARE Proteins; D022603:Shiga Toxins; D013876:Thiophenes; C077239:stxB toxin; D012276:Ricin