title: A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins.
abstract: Botulinum neurotoxins (BoNTs) form a large class of potent and deadly neurotoxins. Given their growing number, it is of paramount importance to discover novel inhibitors targeting common steps of their intoxication process. Recently, EGA was shown to inhibit the action of bacterial toxins and viruses exhibiting a pH-dependent translocation step in mammalian cells, by interfering with their entry route. As BoNTs act in the cytosol of nerve terminals, the entry into an appropriate compartment wherefrom they translocate the catalytic moiety is essential for toxicity. Herein we propose an optimized procedure to synthesize EGA and we show that, in vitro, it prevents the neurotoxicity of different BoNT serotypes by interfering with their trafficking. Furthermore, in mice, EGA mitigates botulism symptoms induced by BoNT/A and significantly decreases the lethality of BoNT/B and BoNT/D. This opens the possibility of using EGA as a lead compound to develop novel inhibitors of botulinum neurotoxins.
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Azarnia Tehran
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Zanetti
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Oneda
authors.initials: O
authors.lastname: Leka
authors.affiliation: Histology and Molecular Biology Section, Army Medical and Veterinary Research Center, Via Santo Stefano Rotondo 4, 00184 Roma, Italy.
authors.forename: Florigio
authors.initials: F
authors.lastname: Lista
authors.affiliation: Histology and Molecular Biology Section, Army Medical and Veterinary Research Center, Via Santo Stefano Rotondo 4, 00184 Roma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fillo
authors.affiliation: Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Binz
authors.affiliation: Public Health England, Porton Down, Salisbury, Wiltshire, SP4 OJG, UK.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Shone
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Rossetto
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.|Italian National Research Council Institute of Neuroscience, University of Padova, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pirazzini
mesh_terms: D000818:Animals; D001692:Biological Transport; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D050600:SNARE Proteins / Q000378:metabolism; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D009498:Neurotoxins; D050600:SNARE Proteins; D012664:Semicarbazones; D001905:Botulinum Toxins