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

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.

Machine-learning guided Venom Induced Dermonecrosis Analysis tooL: VIDAL

“…Vol:. ( 1234567890) www.nature.com/scientificreports/ dermonecrotic lesions with callipers [19][20][21] or the use of manual lesion outlining on transparent plastic sheets and calculation of the encompassed area with millimetric paper 22 . Both of these methods have inherent limitations, as they can only assess entirely spherical areas precisely (which dermonecrotic lesions seldomly are) and are susceptible to potential unconscious bias and human error.…”

“…In the case of tissue sections collected from macroscopically dark lesions, the extent of damage was more pronounced than in macroscopically light lesions. Using the dermonecrosis scoring system developed previously for quantifying lesion severity in H&E-stained lesion cross-sections 19 , the healthy tissue, light lesions, and dark lesions each received mean overall dermonecrosis severity scores of 0.00, 1.73, and 3.50, respectively (Figs. 2, S1).…”

Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform

“…Such treatments could possess several advantages over conventional antivenoms, such as their potential for cross-species neutralisation through generic inhibition of the active site of a class of toxins, improved safety profiles, reduced cost over antibodies, and potential ease of administration ( Clare et al, 2021 ). The efficacy of such drugs has been investigated in the context of both systemic ( Rucavado et al, 2004 ; Arias et al, 2017 ; Lewin et al, 2018a ; Lewin et al, 2018b ; Albulescu et al, 2020a ; Albulescu et al, 2020b ) and local ( Bryan-Quirós et al, 2019 ; Albulescu et al, 2020a ; Hall et al, 2023 ) envenoming in in vivo preclinical models, and in the context of both single drug treatments and combinations of inhibitors targeting different toxin families. Among these, varespladib and its orally bioavailable analogue methyl varespladib have been shown to be highly effective in neutralizing the toxicity of both several viper and elapid venoms in vitro and in vivo ( Lewin et al, 2016 ; Lewin et al, 2018a ; Lewin et al, 2018b ).…”

Harnessing the Cross-Neutralisation Potential of Existing Antivenoms for Mitigating the Outcomes of Snakebite in Sub-Saharan Africa

“…Therefore, there is a pressing need to innovate alternative strategies for treating bites from diverse snake species that can bear an immediate impact. Alternative strategies for snakebite treatment include the use of medicinal plant extracts [14], aptamers [10], peptides [15] and small-molecule inhibitors [16]. In addition, harnessing the cross-neutralisation potential of existing antivenom products could offer an immediate solution to this problem.…”