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

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.

Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins

“…The small size of these compounds, compared with conventional antibodies, confer desirable drug-favorable properties enabling rapid and effective tissue penetration and, depending on the pharmacokinetics and physicochemical properties of specific inhibitors, often make them amenable for oral delivery [61,63,64]. Indeed, both varespladib and DMPS have already been demonstrated to confer preclinical efficacy against snakebite via the oral route [20,63,64]. DMPS is readily absorbed following oral administration in humans, making it a strong candidate for an oral community-based therapy [65]; and there are no major side effects or teratogenic effects that have been reported on DMPS in murine models [66,67].…”

“…Consisting of immunoglobulins purified from hyperimmunized ovine or equine plasma/serum, these products save thousands of lives each year, but are associated with a number of therapeutic challenges, including limited cross-snake species efficacies, poor safety profiles and, for many snakebite victims residing in remote rural areas in developing countries, unacceptable issues with affordability and accessibility [17]. Small molecule toxin inhibitors are regarded as promising candidates for the development of affordable broad-spectrum snakebite treatments, as these can block the enzymatic activities of venoms [18][19][20]. Varespladib, an indole-based nonspecific pan-secretory PLA 2 inhibitor has been studied extensively for repurposing for snakebite.…”

“…The water-soluble, tissue-permeable and licensed metal chelator, 2,3-dimercaptopropane-1-sulfonic acid (DMPS), is also suitable for treating acute and chronic heavy metal intoxication including lead, mercury, cadmium and copper [48,49]. It was recently shown that both dimercaprol and DMPS displayed potential for repurposing as small molecule chelators to treat snake envenoming [20], most probably by chelating and removing Zn 2+ from the active site of Zn 2+ -dependent SVMPs. Of the two drugs, DMPS showed highly promising preclinical efficacy when used as an early oral intervention after envenoming by the SVMP-rich venom of the West African saw-scaled viper (Echis ocellatus), prior to later antivenom treatment with antivenom [20].…”

“…It was recently shown that both dimercaprol and DMPS displayed potential for repurposing as small molecule chelators to treat snake envenoming [20], most probably by chelating and removing Zn 2+ from the active site of Zn 2+ -dependent SVMPs. Of the two drugs, DMPS showed highly promising preclinical efficacy when used as an early oral intervention after envenoming by the SVMP-rich venom of the West African saw-scaled viper (Echis ocellatus), prior to later antivenom treatment with antivenom [20]. In addition to protecting against venom-induced lethality, DMPS was also demonstrated to drastically reduce local venom-induced hemorrhage [20].…”

“…Of the two drugs, DMPS showed highly promising preclinical efficacy when used as an early oral intervention after envenoming by the SVMP-rich venom of the West African saw-scaled viper (Echis ocellatus), prior to later antivenom treatment with antivenom [20]. In addition to protecting against venom-induced lethality, DMPS was also demonstrated to drastically reduce local venom-induced hemorrhage [20]. Thus, marimastat, dimercaprol and DMPS all represent promising candidates for drug repurposing as snakebite therapeutics, as they either inhibit SVMPs or chelate the Zn 2+ ion required for SVMP catalysis.…”