Research ArticleSNAKEBITE

Preclinical validation of a repurposed metal chelator as an early-intervention therapeutic for hemotoxic snakebite

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Science Translational Medicine  06 May 2020:
Vol. 12, Issue 542, eaay8314
DOI: 10.1126/scitranslmed.aay8314

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Biting back against snakebites

Snakebite envenoming is a neglected tropical disease that causes numerous injuries and deaths worldwide. It is difficult to treat because antivenom is unaffordable, not accessible in remote areas, and specific for each individual type of snake. In search of readily available treatments, Albulescu et al. examined a selection of metal chelators that are approved for use in human patients. Treatment with DMPS, a derivative of dimercaprol, was effective against a variety of saw-scaled viper venoms in mouse models when given soon after exposure, suggesting its potential for repurposing as a prehospital treatment. A related Focus by Koh et al. discusses the implications of this study.

Abstract

Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: Echis) leads to systemic hemorrhage and coagulopathy and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity and low affordability and must be administered in clinical settings because of its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially affects patient outcomes after envenoming. Here, we investigated the value of metal ion chelators as prehospital therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS) were found to potently antagonize the activity of Zn2+-dependent snake venom metalloproteinases in vitro. Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also considerably extended survival in a “challenge and treat” model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming. Last, the potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that the safe and affordable repurposed metal chelator DMPS can effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the promise of this drug as an early, prehospital, therapeutic intervention for hemotoxic snakebite envenoming.

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