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 journalArticlepeer-review

17 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 languageEnglish
Article number17513
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 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.

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