TY  - JOUR
PY  - 2024//
TI  - Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib
JO  - Proceedings of the National Academy of Sciences of the United States of America
A1  - Bartlett, Keirah E.
A1  - Hall, Steven R.
A1  - Rasmussen, Sean A.
A1  - Crittenden, Edouard
A1  - Dawson, Charlotte A.
A1  - Albulescu, Laura-Oana
A1  - Laprade, William
A1  - Harrison, Robert A.
A1  - Saviola, Anthony J.
A1  - Modahl, Cassandra M.
A1  - Jenkins, Timothy P.
A1  - Wilkinson, Mark C.
A1  - Gutiérrez, José María
A1  - Casewell, Nicholas R.
SP  - e2315597121
EP  - e2315597121
VL  - 121
IS  - 19
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 0027-8424
UR  - http://dx.doi.org/10.1073/pnas.2315597121
ID  - ref1
ER  -