A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

Laura Oana Albulescu, Chunfang Xie, Stuart Ainsworth, Jaffer Alsolaiss, Edouard Crittenden, Charlotte A. Dawson, Rowan Softley, Keirah E. Bartlett, Robert A. Harrison, Jeroen Kool, Nicholas R. Casewell*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.

Original languageEnglish
Article number6094
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 15 Dec 2020

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