Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite. This damage cannot be effectively prevented with current antivenom treatments, and patients are often left with life-changing wounds. In a new study, researchers from Liverpool School of Tropical Medicine and elsewhere used cellular and mouse experiments to determine which toxins in certain African spitting cobra venom are responsible for causing tissue damage, revealing that a combination of two different types of toxins is required to cause pathology. They then showed that the repurposed drug, varespladib, which targets one of these toxin types, effectively prevents skin and muscle damage in mouse models of envenoming. The findings suggest that varespladib could be an effective type of therapy for preventing snakebite morbidity in Africa.
It is estimated that snakebite causes long-term detrimental effects in around 400,000 people across the world each year, with a substantial proportion of those in Africa the result of spitting cobra bites.
Currently, there is no effective treatment for tackling severe local envenoming caused by spitting cobra venom.
Existing antivenoms only work on bites by other snake species and are often ineffective for treating local envenoming because antivenom antibodies are too large to effectively penetrate into the region around the bite site.
Liverpool School of Tropical Medicine’s Professor Nicholas Casewell and his colleagues discovered that using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage.
“Our findings hold much promise to improve the treatment of tropical snakebite,” Professor Casewell said.
“Current treatments for spitting cobra bites are widely regarded as being ineffective, meaning that rates of disability and amputation have remained high across much of Africa.”
“Our data show that blocking just one of the main toxin families in spitting cobra venom will likely prevent the debilitating tissue damage seen in thousands of snakebite patients each year.”
The study authors first analyzed spitting cobra venom to identify the toxins responsible for causing venom-induced dermonecrosis.
The results showed that cytotoxic three-finger toxins (CTx) are largely responsible but that phospholipases A2 (PLA2) toxins play a critical role in the process.
Local injection of the PLA2-inhibiting drug varespladib reduced the extent of dermonecrosis, even when delivered up to an hour after the venom, and the protection conferred by the drug also extended to venom-induced muscle toxicity.
The findings suggest that varespladib could become an invaluable treatment against the tissue-damaging effects of black-necked and red spitting cobra venoms, which cause extensive morbidity in snakebite victims across the African continent.
“These findings are extremely promising, not only does this offer up a new mode of treatment where previously nothing effective existed, but because varespladib has already gone through testing in human clinical trials, including for snakebite, it could be available for use in real world patients very soon,” said Dr. Keirah Bartlett, also from Liverpool School of Tropical Medicine.
“Snakebite is a devastating neglected tropical disease, with tissue destruction caused by necrotic snake venoms permanently injuring hundreds of thousands of victims every year,” said Dr. Steven Hall, a researcher at Lancaster University.
“Our work shows that the repurposed drug, varespladib, is incredibly effective at inhibiting such necrosis caused by African spitting cobras; an exciting finding as their venoms are particularly fast-acting and destructive.”
“We hope this work helps pave the way to future snakebite therapies that can save the lives and limbs of victims worldwide.”
A paper describing the findings was published in the Proceedings of the National Academy of Sciences.
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Keirah E. Bartlett et al. 2024. Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. PNAS 121 (19): e2315597121; doi: 10.1073/pnas.2315597121