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

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  • Keirah E Bartlett
  • Steve Hall
  • Sean A Rasmussen
  • Edouard Crittenden
  • Charlotte A Dawson
  • Laura-Oana Albulescu
  • William Laprade
  • Robert A Harrison
  • Anthony J Saviola
  • Cassandra Modahl
  • Timothy P. Jenkins
  • Mark C. Wilkinson
  • José María Gutiérrez
  • Nicholas R. Casewell
Article numbere2315597121
<mark>Journal publication date</mark>7/05/2024
<mark>Journal</mark>Proceedings of the National Academy of Sciences of the United States of America
Issue number19
Number of pages12
Pages (from-to)1-12
Publication StatusPublished
Early online date30/04/24
<mark>Original language</mark>English


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.