Drug combination protects mice from the lethal effects of snakebite caused by geographically diverse snake species

News article 10 Dec 2020
“Echis carinatus”:  Saw-scaled vipers, like this Indian species Echis carinatus, are one of the most medically important group of venomous snakes in the world. Photo: Wolfgang Wüster.

Researchers at LSTM’s Centre for Snakebite Research and Interventions (CSRI) have found that a combination of toxin inhibitors could provide the basis of broad-spectrum therapies for the treatment of snakebite caused by distinct snake species

In a paper published in the journal Nature Communications, the team, led by Professor Nick Casewell, explore the potential of using combinations of small molecule toxin inhibitors as broad-spectrum therapeutics against snake venom, and found that a combination of two such inhibitors protects mice against the lethal effects of haemotoxic venoms sourced from multiple species of geographically diverse vipers.

Wolfgang Wüster

First author on the paper is LSTM’s Dr Laura-Oana Albulescu. She said: “In experiments, we observed that combinations of just two drugs, that had both previously undergone phase 3 clinical trials for other conditions, were capable of neutralizing very different viper venoms by inhibiting different toxin families. This is the first time that small molecule inhibitor combinations have been tested preclinically against snake venoms with distinct compositions, and as such it's very encouraging that a two-drug combination has proven to be so effective. This is an exciting development in the move towards new and more effective snakebite treatments.”

Snakebites result in approximately 138,000 deaths a year in the rural communities of sub-Saharan Africa, South and Southeast Asia, and Central and South America. Differences in the composition of snake venoms mean that all existing antibody-based “antivenom” therapies tend to only be effective against bites from specific snake species. Other issues with antivenom, including their high rate of adverse reactions, need to be given intravenously in a healthcare setting, reliance on refrigeration for storage, and high cost to the impoverished snakebite victims of the tropics, mean that they are often inaccessible to those in greatest need. These challenges stimulated the team to explore the potential utility of small molecule toxin inhibitors as new snakebite treatments.

In experiments involving mice, a single dose of a combination of two inhibitors (marimastat and varespladib) was administered 15 minutes after lethal doses of viper venom, and the animals were monitored for 24 hours afterwards. The team found that the combination therapy was capable of protecting the mice from venoms sourced from a range of medically important vipers from Africa, South Asia and Central America, hinting at potential global utility.

The authors conclude that their data provides evidence that combinations of small molecule toxin inhibitors can neutralize a variety of medically important snake venoms. Further preclinical studies are required before such combination therapies progress towards human trials, but these findings suggest small molecule toxin inhibitor therapies could, in the future, provide sorely needed prehospital treatments for snakebites.

 Wolfgang Wüster

Professor Nick Casewell said: “That this two drug combination therapy was capable of neutralising a wide variety of different snake venoms surpassed our expectations. Small molecule drugs show great potential because they should be able to be given to a patient orally via a tablet or capsule soon after a bite, thereby cutting down current life-threatening delays in having to get to an often distant hospital or clinic to receive treatment. They should also be much cheaper to manufacture than existing antivenom, and therefore should be more affordable to tropical snakebite victims. Although lots of work remains to be done, these findings really do highlight the great potential of toxin inhibitors as new snakebite treatments to save lives in some of the world poorest communities.”

Albulescu, LO., Xie, C., Ainsworth, S. et al. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun 11, 6094 (2020). https://doi.org/10.1038/s41467-020-19981-6