biostudies-literatureBartlett KEMedical Research CouncilRoyal SocietyWellcome TrustUKRI | Medical Research Councile2315597121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11087757biostudies-literatureUnknown121(19)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 <i>Naja nigricollis</i> 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.Proceedings of the National Academy of Sciences of the United States of AmericaDermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib.PMC11087757MR/S00016X/1 and MR/L01839X/1NIF\R1\192161221712/Z/20/Z200517/Z/16/ZMC_PC_15040221708/Z/20/Z221712/Z/20/Z and 221708/Z/20/ZJenkins TPAlbulescu LOCasewell NRLaprade WHall SRWilkinson MCHarrison RACrittenden EDawson CASaviola AJRasmussen SAGutierrez JMBartlett KEModahl CMfalseDermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib.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 <i>Naja nigricollis</i> 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.2024-01-01T00:00:00Z2024 May2026-06-01T20:22:21.403Z2026-05-22T03:08:31.872ZS-EPMC110877573868778610.1073/pnas.2315597121