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

Bartlett, Keirah E and Hall, Steve and Rasmussen, Sean A and Crittenden, Edouard and Dawson, Charlotte A and Albulescu, Laura-Oana and Laprade, William and Harrison, Robert A and Saviola, Anthony J and Modahl, Cassandra and Jenkins, Timothy P. and Wilkinson, Mark C. and Gutiérrez, José María and Casewell, Nicholas R. (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, 121 (19): e231559712. pp. 1-12. ISSN 0027-8424

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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 aetiological 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 A2 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 A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa.