A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins

Domenico Azarnia Tehran; Giulia Zanetti; Oneda Leka; Florigio Lista; Silvia Fillo; Thomas Binz; Clifford Shone; Ornella Rossetto; Cesare Montecucco; Cristina Paradisi; Andrea Mattarei; Marco Pirazzini

doi:10.1038/srep17513

A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins

Domenico Azarnia Tehran, Giulia Zanetti, Oneda Leka, Florigio Lista, Silvia Fillo, Thomas Binz, Clifford Shone, Ornella Rossetto, Cesare Montecucco, Cristina Paradisi, Andrea Mattarei, Marco Pirazzini^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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.

Original language	English
Article number	17513
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep17513
Publication status	Published - 16 Dec 2015

Bibliographical note

Funding Information:
We gratefully thank Dr. P. Caccin for performing and evaluating ex vivo experiments. This work was supported by the Italian Ministry of Defence (Progetto PNRM - NIB, Segretariato Generale della Difesa V Reparto), Fondazione CARIPARO “Synaptic Functions and Role of Glial Cells in Brain and Muscle Diseases” to C.M., and a grant from the Ministero dell’Universita e della Ricerca (Progetto PRIN) to O.R.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Access to Document

10.1038/srep17513

Cite this

@article{d8998ebfd88a40df881578e5d1f22956,

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.",

author = "{Azarnia Tehran}, Domenico and Giulia Zanetti and Oneda Leka and Florigio Lista and Silvia Fillo and Thomas Binz and Clifford Shone and Ornella Rossetto and Cesare Montecucco and Cristina Paradisi and Andrea Mattarei and Marco Pirazzini",

note = "Funding Information: We gratefully thank Dr. P. Caccin for performing and evaluating ex vivo experiments. This work was supported by the Italian Ministry of Defence (Progetto PNRM - NIB, Segretariato Generale della Difesa V Reparto), Fondazione CARIPARO “Synaptic Functions and Role of Glial Cells in Brain and Muscle Diseases” to C.M., and a grant from the Ministero dell{\textquoteright}Universita e della Ricerca (Progetto PRIN) to O.R. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.",

year = "2015",

month = dec,

day = "16",

doi = "10.1038/srep17513",

language = "English",

volume = "5",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

}

TY - JOUR

T1 - A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins

AU - Azarnia Tehran, Domenico

AU - Zanetti, Giulia

AU - Leka, Oneda

AU - Lista, Florigio

AU - Fillo, Silvia

AU - Binz, Thomas

AU - Shone, Clifford

AU - Rossetto, Ornella

AU - Montecucco, Cesare

AU - Paradisi, Cristina

AU - Mattarei, Andrea

AU - Pirazzini, Marco

N1 - Funding Information: We gratefully thank Dr. P. Caccin for performing and evaluating ex vivo experiments. This work was supported by the Italian Ministry of Defence (Progetto PNRM - NIB, Segretariato Generale della Difesa V Reparto), Fondazione CARIPARO “Synaptic Functions and Role of Glial Cells in Brain and Muscle Diseases” to C.M., and a grant from the Ministero dell’Universita e della Ricerca (Progetto PRIN) to O.R. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.

PY - 2015/12/16

Y1 - 2015/12/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84949973970&partnerID=8YFLogxK

U2 - 10.1038/srep17513

DO - 10.1038/srep17513

M3 - Article

C2 - 26670952

AN - SCOPUS:84949973970

SN - 2045-2322

VL - 5

JO - Scientific Reports

JF - Scientific Reports

M1 - 17513

ER -

A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this