Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

Date

2015-06-10

Author

Kiriş, Erkan
Stanford, SM
Wanner, LM
Cazares, L
Maestre, MF
Du, HT
Gomba, GY
Burnett, JC
Gussio, R
Bottini, N
Panchal, RG
Kane, CD
Tessarollo, L
Bavari, S

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There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway( s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonismin the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

Subject Keywords

Protein-kinase-C, Synaptosome-associated protein, Differential phosphorylation, Dependent phosphorylation, Tyrosine phosphorylation, Directed differentiation, Neurotransmitter release, Possible involvement, Catalytic domain, Terminal domain

URI

https://hdl.handle.net/11511/41004

Journal

PloS one

DOI

https://doi.org/10.1371/journal.pone.0129264

Collections

Department of Biology, Article

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Citation Formats

E. Kiriş et al., “Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.,” PloS one, 2015, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/41004.