The anticoagulant heparin could be repurposed as a cheap and effective drug to treat cobra bites across Asia and Africa. According to the World Health Organization (WHO), up to 2 million people are envenomed by snakes each year in Asia, while in Africa there are an estimated 435,000 to 580,000 snake bites annually that need treatment.
New Australian research has found the drug can prevent cobra-venom induced necrosis in human cells and mice. Necrosis, the death of tissue around the bite, cannot currently be treated with available antivenoms.
“About 400,000 people survive snakebite but are left with necrotic lesions that can lead to disability and that can have a great effect on livelihood,” says Tian Du, PhD researcher from the Charles Perkins Centre at The University of Sydney and first author of the paper in Science Translational Medicine.
“Cobras are found across mostly Africa and South Asia. In these rural communities where a lot of snake bites occur, either the antivenom can be expensive or the infrastructure and the healthcare system is sometimes not there or too far away for people to get to.”
Du and her colleagues wanted to find a drug that is stable and can be directly injected by a person in the field to treat this necrosis. Through their experiments they landed on heparin: an inexpensive, ubiquitous, WHO-listed “Essential Medicine,” which could be rolled out relatively quickly following successful human trials for this new application.
Snake venom is a cocktail of many deadly compounds. Du says there are 3 general categories: “The ones that attack your heart and cause heart failure; the ones that attack your nervous system; and then tissue damaging, necrotic compounds.”
The team used CRISPR, a gene editing tool that can target and inactivate a gene of interest in a cell, to identify which human genes are involved in the cell-killing effects of spitting cobra venom.
“We look at every single gene in the human genome,” says Du.
“So, you take a large pool of cells, inactivate a different gene in each, add the venom on top, and you can quickly sort of screen and survey which gene is interacting with the venom.”
The team, led by Flinders Professor Greg Neely, used the same approach to identify an antidote to box jellyfish (Chironex fleckeri) venom in 2019.
This time their experiments identified genes involved in the pathway for making heparan sulphate, a long sugar molecule found on the cell surface, are involved in cobra venom-induced cell death.
“What we think is that the venom could be interacting with [heparan sulphate] as an entryway into the cell or to attach itself onto the cell,” says Du.
Heparin and related heparinoid drugs are similar in structure to heparan sulphate, so the venom can bind to them too.
“We can flood the system with lots of heparin and the venom is kind of then overwhelmed with this substance and can’t attach to the [heparan sulphate on the] cell surface,” says Du.
“It’s kind of like a decoy for the venom.”
They showed heparin treatment could promote human cell survival and inhibit cell death after exposure to different cobra venoms, including the African red (Naja pallida) and black-necked (Naja nigricollis) spitting cobra, the monocled cobra (Naja kaouthia), the Chinese cobra (Naja atra) and the Indian spectacled cobra (Naja naja).
A mouse model of a snakebite envenoming showed significant reduction in tissue damage when treated with a “human-equivalent” dose of the FDA-approved heparinoid tinzaparin.
However, because tinzaparin could not completely block venom-induced necrosis, more preclinical research is needed to determine the optimal dose and delivery route to produce a fully effective local antidote.
Du and her colleagues now plan to apply the same whole genome CRISPR “knockout screening” to better understand the action of venoms from other species.
“I’m also looking at blue bottle venom, it’s something that’s relevant to the Australian context, … and at red-bellied black snakes,” says Du.
“We intend to look across species to maybe be able to find broad-acting antidotes in the future.”
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