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: Domenico Azarnia Tehran, Giulia Zanetti, Oneda Leka, Florigio Lista, Silvia Fillo, Thomas Binz, Clifford C Shone, Ornella Rossetto, Cesare Montecucco, Cristina Paradisi, Andrea Mattarei, Marco Pirazzini
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 17513 (Dec 16 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26670952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neurotoxins
• SNARE Proteins
• Semicarbazones
• Botulinum Toxins

Topics

• Animals
• Biological Transport
• Botulinum Toxins (antagonists & inhibitors, metabolism)
• Diaphragm (drug effects, physiopathology)
• Disease Models, Animal
• Male
• Mice
• Neurons (drug effects, metabolism)
• Neurotoxins (antagonists & inhibitors, metabolism)
• Paralysis (drug therapy, etiology, physiopathology)
• Peripheral Nervous System Diseases (drug therapy, etiology, physiopathology)
• SNARE Proteins (metabolism)
• Semicarbazones (chemical synthesis, chemistry, pharmacology)