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.
Bibliographical noteFunding 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.
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