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

• 成果类型: Article
• 署名作者: Bartlett, Keirah E.; Hall, Steven R.; Rasmussen, Sean A.; Crittenden, Edouard; Dawson, Charlotte A.; Albulescu, Laura - Oana; Laprade, William; Harrison, Robert A.; Saviola, Anthony J.; Modahl, Cassandra M.; Jenkins, Timothy P.; Wilkinson, Mark C.; Gutierrez, Jose Maria; Casewell, Nicholas R.
• 署名单位: Liverpool School of Tropical Medicine; Liverpool School of Tropical Medicine; Queen Elizabeth II Health Sciences Centre; Dalhousie University; Technical University of Denmark; University of Colorado System; University of Colorado Anschutz Medical Campus; Technical University of Denmark; Universidad Costa Rica
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9795
• DOI: 10.1073/pnas.2315597121
• 发表日期: 2024-05-07
• 关键词: cytolytic activity; naja-nigricollis; venom; assay; phospholipase-a2; purification; cardiotoxin; necrosis; victims; methyl

摘要

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.