New botulinum neurotoxin constructs for treatment of chronic pain

Leese, C. ORCID: https://orcid.org/0000-0002-3123-0154, Christmas, C. ORCID: https://orcid.org/0009-0009-5129-9982, Mészáros, J. ORCID: https://orcid.org/0000-0002-8196-9061, Ward, S., Maiaru, M. ORCID: https://orcid.org/0000-0003-0927-6567, Hunt, S. P. and Davletov, B. ORCID: https://orcid.org/0000-0003-4658-3275 (2023) New botulinum neurotoxin constructs for treatment of chronic pain. Life Science Alliance, 6 (6). e202201631. ISSN 2575-1077 doi: 10.26508/lsa.202201631

Abstract/Summary

Chronic pain affects one in five people across human societies, with few therapeutic options available. Botulinum neurotoxin (BoNT) can provide long-lasting pain relief by inhibiting local release of neuropeptides and neurotransmitters, but its highly paralytic nature has limited its analgesic potential. Recent advances in protein engineering have raised the possibility of synthesising non-paralysing botulinum molecules for translation to pain sufferers. However, the synthesis of these molecules, via several synthetic steps, has been challenging. Here, we describe a simple platform for safe production of botulinum molecules for treating nerve injury-induced pain. We produced two versions of isopeptide-bonded BoNT from separate botulinum parts using an isopeptide bonding system. Although both molecules cleaved their natural substrate, SNAP25, in sensory neurons, the structurally elongated iBoNT did not cause motor deficit in rats. We show that the non-paralytic elongated iBoNT targets specific cutaneous nerve fibres and provides sustained pain relief in a rat nerve injury model. Our results demonstrate that novel botulinum molecules can be produced in a simple and safe manner and be useful for treating neuropathic pain.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/111661
Identification Number/DOI	10.26508/lsa.202201631
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Uncontrolled Keywords	Animals, Humans, Rats, Neuralgia, Analgesics, Sensory Receptor Cells, Botulinum Toxins, Type A, Chronic Pain
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