FRANCE: ANTI-BIOTERRORISM RESEARCH against RICIN.

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Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge

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Cell, Volume 141, Issue 2, 231-242, 16 April 2010
Copyright 2010 Elsevier Inc. All rights reserved.
10.1016/j.cell.2010.01.043

Referred to by: Ricin Toxin Hits a Retrograde Roadblock

Authors

Bahne Stechmann, Siau-Kun Bai, Emilie Gobbo, Roman Lopez, Goulven Merer, Suzy Pinchard, Laetitia Panigai, Danièle Tenza, Graça Raposo, Bruno Beaumelle, Didier Sauvaire, Daniel Gillet, Ludger Johannes, Julien BarbierSee Affiliations

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Traffic, Signaling, and Delivery Laboratory, Centre de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France Structure and Membrane Compartments Laboratory, Centre de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France Cell and Tissue Imaging Facility (Infrastructures en Biologie Sante et Agronomie), Centre de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, France Laboratoire de Toxinologie Moleculaire et Biotechnologies, Service d'Ingenierie Moleculaire des Proteines, Institut de Biologie et de Technologies de Saclay, Direction des Sciences du Vivant, Commissariat a l'Energie Atomique et aux Energies Alternatives, F-91191 Gif sur Yvette, France Laboratoire de Chimie Bioorganique, Service de Chimie Bio-organique et de Marquage, Institut de Biologie et de Technologies de Saclay, Direction des Sciences du Vivant, Commissariat a l'Energie Atomique et aux Energies Alternatives, F-91191 Gif sur Yvette, France Unite Controles de Bioactivite et Radioanalyse, French Health Products Safety Agency (Afssaps French Official Medicines Control Laboratory), Direction des Laboratoires et des Controles, 635 rue de la Garenne, 34740 Vendargues, France Centre d'etudes d'agents Pathogenes et Biotechnologies pour la Sante, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5236, Case 100, Université Montpellier 2, 34095 Montpellier, France Corresponding author

• Highlights
• 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

Summary

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.