New botulinum neurotoxin constructs for treatment of chronic pain.

Autor:	Leese C; Department of Biomedical Science, University of Sheffield, Sheffield, UK., Christmas C; Department of Biomedical Science, University of Sheffield, Sheffield, UK., Mészáros J; Department of Biomedical Science, University of Sheffield, Sheffield, UK., Ward S; Department of Biomedical Science, University of Sheffield, Sheffield, UK., Maiaru M; Department of Pharmacology, School of Pharmacy, University of Reading, Whiteknights Campus, Reading, UK., Hunt SP; Cell and Developmental Biology, University College London, London, UK., Davletov B; Department of Biomedical Science, University of Sheffield, Sheffield, UK b.davletov@sheffield.ac.uk.; Neuresta, Inc., San Diego, CA, USA.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2023 Apr 11; Vol. 6 (6). Date of Electronic Publication: 2023 Apr 11 (Print Publication: 2023).
DOI:	10.26508/lsa.202201631
Abstrakt:	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. (© 2023 Leese et al.)
Databáze:	MEDLINE
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