Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib

Bartlett, Keirah, Hall, Steven, Rasmussen, Sean A., Crittenden, Edouard, Dawson, Charlotte, Albulescu, Laura-Oana ORCID: https://orcid.org/0000-0001-6563-9217, Laprade, William, Harrison, Robert, Saviola, Anthony J., Modahl, Cassandra, Jenkins, Timothy P., Wilkinson, Mark ORCID: https://orcid.org/0000-0003-3109-6888, Gutiérrez, José María and Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 (2024) 'Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib'. Proceedings of the National Academy of Sciences of the United States of America, Vol 121, Issue 19, e2315597121.

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Abstract

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A 2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A 2 -inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.

Item Type:	Article
Subjects:	QV Pharmacology > QV 38 Drug action. QV Pharmacology > Toxicology > General Toxicology > QV 601 Antidotes and other therapeutic measures WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1073/pnas.2315597121
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	09 May 2024 13:52
Last Modified:	09 May 2024 13:52
URI:	https://archive.lstmed.ac.uk/id/eprint/24535

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