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.
Highlights
Snakebite envenoming is a neglected tropical disease (NTD) that affects ~5 million people worldwide each year, and leads to high mortality (~138,000/year) and morbidity (~400,000500,000/year), in sub-Saharan Africa and southern Asia [1]
Metal chelators inhibit venom activity in vitro Saw-scaled viper venoms are highly enriched in snake venom metalloproteinase (SVMPs) (45.4-72.5% of all toxins), with the exception of that of E. leucogaster, whose venom proteome is dominated by phospholipase A2 (PLA2) (39.7%; SVMPs 27.4%) (Fig. 1)
Because SVMP activity is Zn2+-dependent, we assayed the ability of three metal chelators to inhibit venom SVMPs from six saw-scaled vipers with a wide geographical distribution (Fig. 1), namely E. ocellatus (Nigeria), E. carinatus (U.A.E. and India), E. pyramidum (Kenya), E. leucogaster (Mali), and E. coloratus (Egypt)
Summary
Snakebite envenoming is a neglected tropical disease (NTD) that affects ~5 million people worldwide each year, and leads to high mortality (~138,000/year) and morbidity (~400,000500,000/year), in sub-Saharan Africa and southern Asia [1]. The highest burden of snakebite is suffered by the rural impoverished communities of low and middle income countries, who often rely on agricultural activities for their income [3]. Treatment delays are known to result in poor patient outcomes, and often lead to lifelong disabilities, psychological sequelae, or death [6, 7]. Further compounding this situation, species-specific antivenom, the only appropriate treatment for snakebite [1, 3], is often unavailable locally and, when present, is exceedingly expensive relative to the income of snakebite victims, despite being classified by the WHO as an essential medicine [8]. The WHO has developed a strategy proposed to halve the number of snakebite deaths and disabilities by the year 2030, by improving existing treatments, developing new therapeutics, and empowering local communities to improve pre-hospital treatment [9]
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