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

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 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.

De novo designed proteins neutralize lethal snake venom toxins

“…Similarly, pre-incubation of the cytotoxin binder with isolated cytotoxin from N. pallida (2 IC 50 s) at a 1:5 molar ratio (toxin:binder) gave 85% protection against cytotoxicity (Figure 4c). However, preliminary studies indicated that the CYTX design, in 1:1, 1:2.5, and 1:5 molar ratios (toxin:binder), did not significantly decrease the size of the dermonecrotic lesions induced by intradermal N. nigricollis venom administration in a murine model 55 (Supplementary Fig. S7); the affinity of CYTX likely needs to be further optimized for full in vivo neutralization of cytotoxins.…”

Improving in vivo assays in snake venom and antivenom research: A community discussion

“…60 However, care must be taken in this approach, as recent research has suggested that cell culture models do not accurately recapitulate dermonecrosis. 96 Daboia spp. venoms: The pathophysiology of envenomings by Daboia spp.…”