Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

Tetanus neurotoxin (TeNT) is a protein exotoxin produced by <i>Clostridium tetani</i> 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) a...

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Autores principales:	Giulia Zanetti, Andrea Mattarei, Florigio Lista, Ornella Rossetto, Cesare Montecucco, Marco Pirazzini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tetanus neurotoxin trafficking disulfide reduction thioredoxin system inhibitors EGA Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/63b35b43dab140a88f7cfa13188faf6a
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spelling	oai:doaj.org-article:63b35b43dab140a88f7cfa13188faf6a2021-11-25T18:39:36ZNovel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin10.3390/ph141111341424-8247https://doaj.org/article/63b35b43dab140a88f7cfa13188faf6a2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1134https://doaj.org/toc/1424-8247Tetanus neurotoxin (TeNT) is a protein exotoxin produced by <i>Clostridium tetani</i> 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.Giulia ZanettiAndrea MattareiFlorigio ListaOrnella RossettoCesare MontecuccoMarco PirazziniMDPI AGarticletetanus neurotoxintraffickingdisulfide reductionthioredoxin system inhibitorsEGAMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1134, p 1134 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tetanus neurotoxin trafficking disulfide reduction thioredoxin system inhibitors EGA Medicine R Pharmacy and materia medica RS1-441
spellingShingle	tetanus neurotoxin trafficking disulfide reduction thioredoxin system inhibitors EGA Medicine R Pharmacy and materia medica RS1-441 Giulia Zanetti Andrea Mattarei Florigio Lista Ornella Rossetto Cesare Montecucco Marco Pirazzini Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin
description	Tetanus neurotoxin (TeNT) is a protein exotoxin produced by <i>Clostridium tetani</i> 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.
format	article
author	Giulia Zanetti Andrea Mattarei Florigio Lista Ornella Rossetto Cesare Montecucco Marco Pirazzini
author_facet	Giulia Zanetti Andrea Mattarei Florigio Lista Ornella Rossetto Cesare Montecucco Marco Pirazzini
author_sort	Giulia Zanetti
title	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_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_sort	novel small molecule inhibitors that prevent the neuroparalysis of tetanus neurotoxin
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/63b35b43dab140a88f7cfa13188faf6a
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Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

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