Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication

Schnell, Leonie; Mittler, Ann‐Katrin; Mattarei, Andrea; Tehran, Domenico Azarnia; Montecucco, Cesare; Barth, Holger

doi:10.3390/toxins8070221

Cited by 11 publications

(10 citation statements)

References 40 publications

(37 reference statements)

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“…No other transition state analogues have been explored for this toxin, although there are reports of inhibition of uptake by amine compounds and semicarbazoles. 135–137…”

Section: Bacterial Adp-ribosylating Toxins and Their Transition Statesmentioning

confidence: 99%

Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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Transition state theory teaches that chemically stable mimics of enzymatic transition states will bind tightly to their cognate enzymes. Kinetic isotope effects combined with computational quantum chemistry provides enzymatic transition state information with sufficient fidelity to design transition state analogues. Examples are selected from various stages of drug development to demonstrate the application of transition state theory, inhibitor design, physicochemical characterization of transition state analogues, and their progress in drug development.

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“…No other transition state analogues have been explored for this toxin, although there are reports of inhibition of uptake by amine compounds and semicarbazoles. 135–137…”

Section: Bacterial Adp-ribosylating Toxins and Their Transition Statesmentioning

confidence: 99%

Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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“…The tox + phage may convert non-toxinogenic C. diphtheriae, C. ulcerans , and C. pseudotuberculosis to toxinogenic bacteria (Buck et al, 1985 ; Naglich et al, 1992 ). In a recent work (Schnell et al, 2016 ), diphtheria toxin (DT, 58 kDa), which is the causative agent of diphtheria is efficiently taken up into human cells and its catalytic domain (DTA, 21 kDa) acts as an extremely potent enzyme in the cytosol. Histidines residues (diphthamide) are modified by DTA covalently transfers, inhibiting protein synthesis and causing cell death.…”

Section: Virulence Factorsmentioning

confidence: 99%

“…In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death (Schnell et al, 2016 ).…”

Section: Virulence Factorsmentioning

confidence: 99%

Insight of Genus Corynebacterium: Ascertaining the Role of Pathogenic and Non-pathogenic Species

Oliveira

Aburjaile

et al. 2017

Front. Microbiol.

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This review gathers recent information about genomic and transcriptomic studies in the Corynebacterium genus, exploring, for example, prediction of pathogenicity islands and stress response in different pathogenic and non-pathogenic species. In addition, is described several phylogeny studies to Corynebacterium, exploring since the identification of species until biological speciation in one species belonging to the genus Corynebacterium. Important concepts associated with virulence highlighting the role of Pld protein and Tox gene. The adhesion, characteristic of virulence factor, was described using the sortase mechanism that is associated to anchorage to the cell wall. In addition, survival inside the host cell and some diseases, were too addressed for pathogenic corynebacteria, while important biochemical pathways and biotechnological applications retain the focus of this review for non-pathogenic corynebacteria. Concluding, this review broadly explores characteristics in genus Corynebacterium showing to have strong relevance inside the medical, veterinary, and biotechnology field.

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“…Considering the importance of CNTs trafficking upon entry into nerve terminals, we also tested EGA, a compound that was found to interfere with the intracellular vesicular trafficking of several pathogens [47,[49][50][51].…”

Section: Ega Prevents Tent-induced Cleavage Of Vamp-2 In Cultured Neuronsmentioning

confidence: 99%

Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

Zanetti

Mattarei

Lista³

et al. 2021

Pharmaceuticals

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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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Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication

Cited by 11 publications

References 40 publications

Enzymatic Transition States and Drug Design

Enzymatic Transition States and Drug Design

Insight of Genus Corynebacterium: Ascertaining the Role of Pathogenic and Non-pathogenic Species

Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

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