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

Albulescu, Laura-Oana ORCID: https://orcid.org/0000-0001-6563-9217, Hales, MS, Ainsworth, Stuart ORCID: https://orcid.org/0000-0002-0199-6482, Al Solaiss, Jaffer, Crittenden, Edouard, Calvete, Juan, Evans, Chloe, Wilkinson, Mark ORCID: https://orcid.org/0000-0003-3109-6888, Harrison, Robert, Kool, Jeroen and Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 (2020) 'Preclinical validation of a repurposed metal chelator as an early intervention therapeutic for hemotoxic snakebite'. Science Translational Medicine, Vol 12, Issue 542, eaay8314.

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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, low affordability, and must be administered in clinical settings due to its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially impacts on patient outcomes after envenoming. Here we investigated the value of metal ion chelators as pre-hospital 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. Finally, 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 highlights the promise of this drug as an early, pre-hospital, therapeutic intervention for hemotoxic snakebite envenoming.

Item Type:	Article
Subjects:	QV Pharmacology > Heavy Metals. Gases > QV 290 Heavy metals and their compounds WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 400 General works WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 140 Hematopoietic system and hematopoiesis. Developmental theories. Blood cells (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1126/scitranslmed.aay8314
Depositing User:	Mary Creegan
Date Deposited:	07 May 2020 13:57
Last Modified:	21 Jul 2022 10:41
URI:	https://archive.lstmed.ac.uk/id/eprint/14032

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