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

Author

Listed:
  • Steven R. Hall

    (Liverpool School of Tropical Medicine, Pembroke Place
    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
    Liverpool School of Tropical Medicine, Pembroke Place)

  • Jeroen Kool

    (Vrije Universiteit Amsterdam
    Centre for Analytical Sciences Amsterdam (CASA))

  • José María Gutiérrez

    (Universidad de Costa Rica)

  • Nicholas R. Casewell

    (Liverpool School of Tropical Medicine, Pembroke Place
    Liverpool School of Tropical Medicine, Pembroke Place)

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.

Suggested Citation

  • 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 & Nicholas R. Casewel, 2023. "Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43510-w
    DOI: 10.1038/s41467-023-43510-w
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    References listed on IDEAS

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    1. David J Williams & Mohd Abul Faiz & Bernadette Abela-Ridder & Stuart Ainsworth & Tommaso C Bulfone & Andrea D Nickerson & Abdulrazaq G Habib & Thomas Junghanss & Hui Wen Fan & Michael Turner & Robert , 2019. "Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming," PLOS Neglected Tropical Diseases, Public Library of Science, vol. 13(2), pages 1-12, February.
    2. Laura-Oana Albulescu & Chunfang Xie & Stuart Ainsworth & Jaffer Alsolaiss & Edouard Crittenden & Charlotte A. Dawson & Rowan Softley & Keirah E. Bartlett & Robert A. Harrison & Jeroen Kool & Nicholas , 2020. "A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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