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Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

Tetanus neurotoxin (TeNT) is a protein exotoxin produced by Clostridium tetani that causes the deadly spastic neuroparalysis of tetanus. It consists of a metalloprotease light chain and of a heavy chain linked via a disulphide bond. TeNT binds to the neuromuscular junction (NMJ) and it is retro-axon...

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Autores principales: Zanetti, Giulia, Mattarei, Andrea, Lista, Florigio, Rossetto, Ornella, Montecucco, Cesare, Pirazzini, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618345/
https://www.ncbi.nlm.nih.gov/pubmed/34832916
http://dx.doi.org/10.3390/ph14111134
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author Zanetti, Giulia
Mattarei, Andrea
Lista, Florigio
Rossetto, Ornella
Montecucco, Cesare
Pirazzini, Marco
author_facet Zanetti, Giulia
Mattarei, Andrea
Lista, Florigio
Rossetto, Ornella
Montecucco, Cesare
Pirazzini, Marco
author_sort Zanetti, Giulia
collection PubMed
description Tetanus neurotoxin (TeNT) is a protein exotoxin produced by Clostridium tetani that causes the deadly spastic neuroparalysis of tetanus. It consists of a metalloprotease light chain and of a heavy chain linked via a disulphide bond. TeNT binds to the neuromuscular junction (NMJ) and it is retro-axonally transported into vesicular compartments to the spinal cord, where it is released and taken up by inhibitory interneuron. Therein, the catalytic subunit is translocated into the cytoplasm where it cleaves its target protein VAMP-1/2 with consequent blockage of the release of inhibitory neurotransmitters. Vaccination with formaldehyde inactivated TeNT prevents the disease, but tetanus is still present in countries where vaccination coverage is partial. Here, we show that small molecule inhibitors interfering with TeNT trafficking or with the reduction of the interchain disulphide bond block the activity of the toxin in neuronal cultures and attenuate tetanus symptoms in vivo. These findings are relevant for the development of therapeutics against tetanus based on the inhibition of toxin molecules that are being retro-transported to or are already within the spinal cord and are, thus, not accessible to anti-TeNT immunoglobulins.
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spelling pubmed-86183452021-11-27 Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin Zanetti, Giulia Mattarei, Andrea Lista, Florigio Rossetto, Ornella Montecucco, Cesare Pirazzini, Marco Pharmaceuticals (Basel) Communication Tetanus neurotoxin (TeNT) is a protein exotoxin produced by Clostridium tetani that causes the deadly spastic neuroparalysis of tetanus. It consists of a metalloprotease light chain and of a heavy chain linked via a disulphide bond. TeNT binds to the neuromuscular junction (NMJ) and it is retro-axonally transported into vesicular compartments to the spinal cord, where it is released and taken up by inhibitory interneuron. Therein, the catalytic subunit is translocated into the cytoplasm where it cleaves its target protein VAMP-1/2 with consequent blockage of the release of inhibitory neurotransmitters. Vaccination with formaldehyde inactivated TeNT prevents the disease, but tetanus is still present in countries where vaccination coverage is partial. Here, we show that small molecule inhibitors interfering with TeNT trafficking or with the reduction of the interchain disulphide bond block the activity of the toxin in neuronal cultures and attenuate tetanus symptoms in vivo. These findings are relevant for the development of therapeutics against tetanus based on the inhibition of toxin molecules that are being retro-transported to or are already within the spinal cord and are, thus, not accessible to anti-TeNT immunoglobulins. MDPI 2021-11-08 /pmc/articles/PMC8618345/ /pubmed/34832916 http://dx.doi.org/10.3390/ph14111134 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Zanetti, Giulia
Mattarei, Andrea
Lista, Florigio
Rossetto, Ornella
Montecucco, Cesare
Pirazzini, Marco
Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title_full Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title_fullStr Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title_full_unstemmed Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title_short Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
title_sort novel small molecule inhibitors that prevent the neuroparalysis of tetanus neurotoxin
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618345/
https://www.ncbi.nlm.nih.gov/pubmed/34832916
http://dx.doi.org/10.3390/ph14111134
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