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

Proc Natl Acad Sci U S A. 2024 May 7;121(19):e2315597121. doi: 10.1073/pnas.2315597121. Epub 2024 Apr 30.


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 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 therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.

Keywords: drug repurposing; neglected tropical diseases; snakebite envenoming; toxins; venoms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetates*
  • Acrylamides / pharmacology
  • Animals
  • Drug Repositioning
  • Elapid Venoms*
  • Elapidae
  • Humans
  • Indoles*
  • Keratinocytes / drug effects
  • Keto Acids*
  • Mice
  • Naja
  • Necrosis*
  • Phospholipases A2 / metabolism
  • Skin / drug effects
  • Skin / pathology
  • Snake Bites* / drug therapy


  • Elapid Venoms
  • varespladib
  • Keto Acids
  • Acrylamides
  • Phospholipases A2
  • Acetates
  • Indoles