Citation

Bartlett KE, Hall SR, Rasmussen SA, Crittenden E, Dawson CA, Albulescu LO, Laprade W, Harrison RA, Saviola AJ, Modahl CM, Jenkins TP, Wilkinson MC, Gutiérrez JM, Casewell NR. Proc. Natl. Acad. Sci. U. S. A. 2024; 121(19): e2315597121.

Copyright

(Copyright © 2024, National Academy of Sciences)

DOI

10.1073/pnas.2315597121

PMID

38687786

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.

Language: en

Keywords

Humans; Animals; *Acetates; *Elapid Venoms; *Indoles; *Keto Acids; *Necrosis; *Snake Bites/drug therapy; Acrylamides/pharmacology; Drug Repositioning; drug repurposing; Elapidae; Keratinocytes/drug effects; Mice; Naja; neglected tropical diseases; Phospholipases A2/metabolism; Skin/drug effects/pathology; snakebite envenoming; toxins; venoms