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 and Nicholas R. Casewell ()
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Laura-Oana Albulescu: Liverpool School of Tropical Medicine
Chunfang Xie: Vrije Universiteit Amsterdam
Stuart Ainsworth: Liverpool School of Tropical Medicine
Jaffer Alsolaiss: Liverpool School of Tropical Medicine
Edouard Crittenden: Liverpool School of Tropical Medicine
Charlotte A. Dawson: Liverpool School of Tropical Medicine
Rowan Softley: Liverpool School of Tropical Medicine
Keirah E. Bartlett: Liverpool School of Tropical Medicine
Robert A. Harrison: Liverpool School of Tropical Medicine
Jeroen Kool: Vrije Universiteit Amsterdam
Nicholas R. Casewell: Liverpool School of Tropical Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19981-6

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