Small Molecule Receptor Binding Inhibitors with In Vivo Efficacy against Botulinum Neurotoxin Serotypes A and E

Botulinum neurotoxins (BoNTs) are the most poisonous substances in nature. Currently, the only therapy for botulism is antitoxin. This therapy suffers from several limitations and hence new therapeutic strategies are desired. One of the limitations in discovering BoNT inhibitors is the absence of an...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-08, Vol.22 (16), p.8577
Main Authors: Ben David, Alon, Barnea, Ada, Diamant, Eran, Dor, Eyal, Schwartz, Arieh, Torgeman, Amram, Zichel, Ran
Format: Article
Language:English
Subjects:
Antibodies
Assaying
Aurintricarboxylic acid
Binding
Botulinum toxin
Botulism
Enzymes
Galactosidase
Glutathione transferase
High-throughput screening
Horses
Inhibitors
Intoxication
Laboratories
Lethal dose
Neurotoxins
Protein 2C
Proteins
Serotypes
Toxins
β-Galactosidase
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Summary:Botulinum neurotoxins (BoNTs) are the most poisonous substances in nature. Currently, the only therapy for botulism is antitoxin. This therapy suffers from several limitations and hence new therapeutic strategies are desired. One of the limitations in discovering BoNT inhibitors is the absence of an in vitro assay that correlates with toxin neutralization in vivo. In this work, a high-throughput screening assay for receptor-binding inhibitors against BoNT/A was developed. The assay is composed of two chimeric proteins: a receptor-simulating protein, consisting of the fourth luminal loop of synaptic vesicle protein 2C fused to glutathione-S-transferase, and a toxin-simulating protein, consisting of the receptor-binding domain of BoNT/A fused to beta-galactosidase. The assay was applied to screen the LOPAC1280 compound library. Seven selected compounds were evaluated in mice exposed to a lethal dose of BoNT/A. The compound aurintricarboxylic acid (ATA) conferred 92% protection, whereas significant delayed time to death (p < 0.005) was observed for three additional compounds. Remarkably, ATA was also fully protective in mice challenged with a lethal dose of BoNT/E, which also uses the SV2 receptor. This study demonstrates that receptor-binding inhibitors have the potential to serve as next generation therapeutics for botulism, and therefore the assay developed may facilitate discovery of new anti-BoNT countermeasures.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22168577