title: Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Leishmania and Chlamydiales.
abstract: Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use.
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Neetu
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Noël
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Goudet
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Hinsinger
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Michau
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Pons
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Hajer
authors.initials: H
authors.lastname: Abdelkafi
authors.affiliation: INSERM, UMR1043, CPTP, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Secher
authors.affiliation: INSERM, UMR1043, CPTP, Toulouse, France.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Shima
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Olena
authors.initials: O
authors.lastname: Shtanko
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076, CNRS BioCIS, LabEx LERMIT, Université Paris-Sud, Université Paris-Saclay, F-92290, Chatenay-Malabry, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cojean
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076, CNRS BioCIS, LabEx LERMIT, Université Paris-Sud, Université Paris-Saclay, F-92290, Chatenay-Malabry, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pomel
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076, CNRS BioCIS, LabEx LERMIT, Université Paris-Sud, Université Paris-Saclay, F-92290, Chatenay-Malabry, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Liévin-Le Moal
authors.affiliation: DRUGABILIS (French Research Performer SME), F-92290, Chatenay-Malabry, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Leignel
authors.affiliation: University of Würzburg, Biocenter, Chair of Microbiology, Am Hubland, D-97074, Würzburg, Germany.
authors.forename: Jo-Ana
authors.initials: JA
authors.lastname: Herweg
authors.affiliation: University of Würzburg, Biocenter, Chair of Microbiology, Am Hubland, D-97074, Würzburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Institut Curie, PSL Research University, Endocytic Trafficking and Therapeutic Delivery Group, 26 rue d'Ulm, F-75248, Paris Cedex 05, France; CNRS, UMR3666, F-75005, Paris, France; INSERM, U1143, F-75005, Paris, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian, EH25 9RG, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Harrison
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian, EH25 9RG, United Kingdom; The Pirbright Institute, Ash Rd, Pirbright, Surrey GH24 0NF, United Kingdom.
authors.forename: Philippa M
authors.initials: PM
authors.lastname: Beard
authors.affiliation: ImmunoPharmacology and Biosafety Laboratory, BERTIN Pharma, CEA, F-92265, Fontenay-aux-Roses, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, U1184, Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Infrastructure, F-92265, Fontenay-aux-Roses, France; INSERM, U1184, F-94276, Le Kremlin-Bicêtre, France; University of Paris South, U1184, F-92265, Fontenay-aux-Roses, France; Vaccine Research Institute, Henri Mondor Hospital, F-94010, Créteil, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Le Grand
authors.affiliation: Infectious Disease Research, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Rayner
authors.affiliation: University of Würzburg, Biocenter, Chair of Microbiology, Am Hubland, D-97074, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
authors.affiliation: DRUGABILIS (French Research Performer SME), F-92290, Chatenay-Malabry, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Vacus
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076, CNRS BioCIS, LabEx LERMIT, Université Paris-Sud, Université Paris-Saclay, F-92290, Chatenay-Malabry, France.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.affiliation: INSERM, UMR1043, CPTP, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cintrat
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Barbier
authors.affiliation: Institute of Biology and Technology of Saclay (IBITECS), CEA, LabEx LERMIT, Université Paris-Saclay, F-91191, Gif Sur Yvette, France. Electronic address: Daniel.GILLET@cea.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gillet
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002695:Chlamydiales / Q000187:drug effects / Q000378:metabolism*; D029043:Ebolavirus / Q000187:drug effects / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D007891:Leishmania / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000494:pharmacology; D023421:Models, Animal; D000067996:RAW 264.7 Cells; D012276:Ricin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022603:Shiga Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; D001549:Benzamides; D022603:Shiga Toxins; D013876:Thiophenes; D016685:Mitomycin; D012276:Ricin
keywords: Bioterrorism; Biothreat agents; Emerging infectious diseases; High-throughput cell-based assays; Retrograde cell transport; Ricin toxin; Shiga-like toxins