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

Albulescu, Laura-Oana, Xie, C, Ainsworth, Stuart ORCID: https://orcid.org/0000-0002-0199-6482, Alsolaiss, Jaffar, Crittenden, Edouard, Dawson, Charlotte, Softley, R, Bartlett, Keirah, Harrison, Robert, Kool, J and Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 (2020) 'A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite'. Nature communications, Vol 11, Issue 6094.

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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.

Item Type: Article
Subjects: QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 630 Toxins. Antitoxins
WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1038/s41467-020-19981-6
Depositing User: Mary Creegan
Date Deposited: 16 Dec 2020 12:24
Last Modified: 16 Dec 2020 12:24
URI: https://archive.lstmed.ac.uk/id/eprint/16084

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