title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
abstract: 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.
authors.affiliation: Traffic, Signaling, and Delivery Laboratory, Centre de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Bahne
authors.initials: B
authors.lastname: Stechmann
authors.forename: Siau-Kun
authors.initials: SK
authors.lastname: Bai
authors.forename: Emilie
authors.initials: E
authors.lastname: Gobbo
authors.forename: Roman
authors.initials: R
authors.lastname: Lopez
authors.forename: Goulven
authors.initials: G
authors.lastname: Merer
authors.forename: Suzy
authors.initials: S
authors.lastname: Pinchard
authors.forename: Laetitia
authors.initials: L
authors.lastname: Panigai
authors.forename: Danièle
authors.initials: D
authors.lastname: Tenza
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Bruno
authors.initials: B
authors.lastname: Beaumelle
authors.forename: Didier
authors.initials: D
authors.lastname: Sauvaire
authors.forename: Daniel
authors.initials: D
authors.lastname: Gillet
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.forename: Julien
authors.initials: J
authors.lastname: Barbier
mesh_terms: 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
chemical_list: 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