Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Steven R. Hall, Sean A. Rasmussen, Edouard Crittenden, Charlotte A. Dawson, Keirah E. Bartlett, Adam P. Westhorpe, Laura-Oana Albulescu, Jeroen Kool, José María Gutiérrez and Nicholas R. Casewell ()
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Steven R. Hall: Liverpool School of Tropical Medicine, Pembroke Place
Sean A. Rasmussen: Queen Elizabeth II Health Sciences Centre and Dalhousie University, 7th Floor of MacKenzie Building
Edouard Crittenden: Liverpool School of Tropical Medicine, Pembroke Place
Charlotte A. Dawson: Liverpool School of Tropical Medicine, Pembroke Place
Keirah E. Bartlett: Liverpool School of Tropical Medicine, Pembroke Place
Adam P. Westhorpe: Liverpool School of Tropical Medicine, Pembroke Place
Laura-Oana Albulescu: Liverpool School of Tropical Medicine, Pembroke Place
Jeroen Kool: Vrije Universiteit Amsterdam
José María Gutiérrez: Universidad de Costa Rica
Nicholas R. Casewell: Liverpool School of Tropical Medicine, Pembroke Place

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

Date: 2023
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DOI: 10.1038/s41467-023-43510-w

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