Department of Biomedical Sciences, Via U. Bassi 58/B, 35121, Padova, Italy.
Histology and Molecular Biology Section, Army Medical and Veterinary Research Center, Via Santo Stefano Rotondo 4, 00184 Roma, Italy.
Sci Rep. 2015 Dec 16;5:17513. doi: 10.1038/srep17513.
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.
肉毒神经毒素（BoNTs）是一大类强效且致命的神经毒素。鉴于它们的数量不断增加，发现针对其中毒过程共同步骤的新型抑制剂至关重要。最近，EGA 被证明可以通过干扰其进入途径来抑制在哺乳动物细胞中具有 pH 依赖性易位步骤的细菌毒素和病毒的作用。由于 BoNTs 在神经末梢的细胞质中起作用，因此进入适当的隔室，从那里它们易位催化部分对于毒性至关重要。本文提出了一种优化的 EGA 合成方法，并证明它可以通过干扰其运输来防止不同 BoNT 血清型的神经毒性。此外，在小鼠中，EGA 减轻了由 BoNT/A 诱导的肉毒中毒症状，并显著降低了 BoNT/B 和 BoNT/D 的致死率。这为使用 EGA 作为开发新型肉毒神经毒素抑制剂的先导化合物开辟了可能性。
