title: Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication.
abstract: Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany. leonie.schnell@uni-ulm.de.
authors.forename: Leonie
authors.initials: L
authors.lastname: Schnell
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany. ann-katrin.mittler@uni-ulm.de.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Mittler
authors.affiliation: Department of Chemical Sciences, University of Padova, 35121 Padova, Italy. andrea.mattarei@unipd.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy. doazte@gmail.com.
authors.forename: Domenico
authors.initials: D
authors.lastname: Azarnia Tehran
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy. cesare.montecucco@gmail.com.
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany. holger.barth@uni-ulm.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
mesh_terms: D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D004167:Diphtheria Toxin / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020011:Protective Agents / Q000494:pharmacology*; D012664:Semicarbazones / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D004167:Diphtheria Toxin; D020011:Protective Agents; D012664:Semicarbazones; C000624527:semicarbazone EGA
keywords: EGA; cellular uptake; diphtheria; diphtheria toxin; membrane transport