Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Chlamydiales and Leishmania

N. Gupta, R. Noël, A. Goudet, K. Hinsinger, A. Michau, V. Pons, H. Abdelkafi, T. Secher, A. Shima, O. Shtanko, Y. Sakurai, S. Cojean, S. Pomel, V. Liévin-le Moal, V. Leignel, J.-a. Herweg, A. Fischer, L. Johannes, Kate Harrison, Philippa M. BeardP. Clayette, R. Le Grand, J.o. Rayner, T. Rudel, J. Vacus, P.m. Loiseau, R.a. Davey, E. Oswald, J.-c. Cintrat, J. Barbier, D. Gillet

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)96-103
JournalChemico-Biological interactions
Volume267
Early online date3 Oct 2016
DOIs
Publication statusPublished - 1 Apr 2017

Keywords

  • Bioterrorism
  • Biothreat agents
  • Emerging infectious diseases
  • Ricin toxin
  • Shiga-like toxins
  • Retrograde cell transport
  • High-throughput cell-based assays

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