Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons

Corrie, Eve; Bresnahan, Rebecca; Doran, Ciara; Leese, Charlotte; Balmforth, Matthew R.; Andreou, Anna; Zhantleuova, Aisha; Seward, Elizabeth P.; Webb, Michael E.; Turnbull, W. Bruce; Davletov, Bazbek

doi:10.3390/toxins18040174

Open AccessArticle

Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons

by

Eve Corrie

^1,†

,

Rebecca Bresnahan

^1,†,

Ciara Doran

^1,†,

Charlotte Leese

^1,†,

Matthew R. Balmforth

^2,†

,

Anna Andreou

³

,

Aisha Zhantleuova

⁴,

Elizabeth P. Seward

¹

,

Michael E. Webb

²,

W. Bruce Turnbull

²

and

Bazbek Davletov

^1,4,*

¹

School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK

²

School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK

³

Headache Research, Wolfson Sensory, Pain and Regeneration Centre, King’s College London, London SE1 1UL, UK

⁴

Department of Biophysics, Biomedicine and Neuroscience, Al-Farabi Kazakh National University, Almaty A15E3C7, Kazakhstan

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Toxins 2026, 18(4), 174; https://doi.org/10.3390/toxins18040174

Submission received: 19 January 2026 / Revised: 27 March 2026 / Accepted: 31 March 2026 / Published: 3 April 2026

(This article belongs to the Special Issue Botulinum Neurotoxins for the Treatment of Chronic Pain and Headaches)

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Abstract

Botulinum neurotoxin injections are used off-label to treat chronic pain, but their efficacy is limited and paralytic effects restrict clinical utility in these applications. Here, we investigated whether combining the light chain and translocation domains of botulinum neurotoxin A (BoNT/A) with the GM1-binding B subunit of cholera toxin would be beneficial in silencing pain-associated sensory neurons. Chimeric ChoBot was assembled via a coiled-coil linking technology and was shown to retain the enzymatic activity of BoNT/A in vitro and in vivo. In cultured dorsal root ganglion neurons, ChoBot cleaved SNAP25 in a calcitonin gene-related peptide (CGRP)-rich subpopulation of sensory neurons, resulting in marked inhibition of CGRP release. ChoBot had a lesser effect on the compound muscle action potentials of the rat gastrocnemius muscle than BoNT/A following subcutaneous injections. In rat models of pain, including chemotherapy-induced peripheral neuropathy, intraplantar administration of ChoBot significantly attenuated mechanical allodynia. Immunohistochemical analysis confirmed SNAP25 cleavage in NF200- and CGRP-expressing sensory fibres in the epidermis following a single injection. ChoBot also mediated SNAP25 cleavage in human neuroblastoma cells in culture. Together, these findings indicate that ChoBot enables a silencing of pain-associated sensory pathways, providing a new strategy for the development of new long-lasting analgesics for chronic pain.

Keywords: botulinum neurotoxin; cholera toxin; neuropathic pain; chimeric toxin; calcitonin gene-related peptide (CGRP); analgesic

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MDPI and ACS Style

Corrie, E.; Bresnahan, R.; Doran, C.; Leese, C.; Balmforth, M.R.; Andreou, A.; Zhantleuova, A.; Seward, E.P.; Webb, M.E.; Turnbull, W.B.; et al. Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons. Toxins 2026, 18, 174. https://doi.org/10.3390/toxins18040174

AMA Style

Corrie E, Bresnahan R, Doran C, Leese C, Balmforth MR, Andreou A, Zhantleuova A, Seward EP, Webb ME, Turnbull WB, et al. Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons. Toxins. 2026; 18(4):174. https://doi.org/10.3390/toxins18040174

Chicago/Turabian Style

Corrie, Eve, Rebecca Bresnahan, Ciara Doran, Charlotte Leese, Matthew R. Balmforth, Anna Andreou, Aisha Zhantleuova, Elizabeth P. Seward, Michael E. Webb, W. Bruce Turnbull, and et al. 2026. "Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons" Toxins 18, no. 4: 174. https://doi.org/10.3390/toxins18040174

APA Style

Corrie, E., Bresnahan, R., Doran, C., Leese, C., Balmforth, M. R., Andreou, A., Zhantleuova, A., Seward, E. P., Webb, M. E., Turnbull, W. B., & Davletov, B. (2026). Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons. Toxins, 18(4), 174. https://doi.org/10.3390/toxins18040174

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Cholera Toxin-Mediated Targeting of Botulinum Neurotoxin Activity to Pain-Associated Sensory Neurons

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