Antithrombotic drug could protect against damage caused by cobra venom

Orange-red in colour, native to Tanzania Nadja Perl The Red Spitting Cobra is a formidable opponent, measuring 1.2 metres in length. When threatened, it raises its hood and hisses loudly. If this intimidation fails to deter the predator, it opens its mouth. The muscles around the snake's venom glands contract, spurting venom into the threat's eyes, nose and mouth. As the victim's face burns with pain, the cobra uses the opportunity to lunge forward and bite, pumping a flood of venom into the victim's body.

The venom attacks cells in the body and damages the nervous system, almost always resulting in death for the cobra's frequent victims – toads, frogs, birds and other snakes. Humans may be lucky enough to survive, but they will suffer permanent disabilities.

Unfavorable bargains on antitoxins

Encounters with venomous snakes kill around 140,000 people each year, especially in tropical regions of Africa and Asia. Despite this staggering figure, treatments for snakebites remain outdated.

Based on work by French scientists in the late 1800s, today antivenoms are made by injecting small amounts of snake venom into livestock such as horses and sheep, which activates the animals' immune systems to produce antibodies that neutralize the venom. Researchers extract these antibodies from the animals' blood, refrigerate it, and ship it to hospitals to inject into snakebite victims.

Antitoxins are difficult to produce, store, transport and administer, are expensive and can cause serious side effects in humans, some of which can be fatal.

That could soon change, according to a study published in the journal Neurology in July 2024. Science Translational MedicineA team of scientists from Australia, the UK, Canada and Costa Rica reported The drug tinzaparin, commonly used to prevent blood clots, was found to significantly reduce the damage to cells caused by cobra venom, and the team also found that the drug was able to reduce damage to the skin of mice injected with venom.

be press releaseThe scientists have filed a patent and may begin human clinical trials soon.

“This discovery could pave the way for practical solutions for regions with the highest snakebite morbidity,” said Kartik Sunagar, an associate professor who studies snake venom evolution and advanced snakebite medicines at the Centre for Ecological Sciences at the Indian Institute of Science (IISc), Bengaluru.

How toxins kill cells

The venom of two of the species the researchers used in their study, the red-necked and black-necked cobra, is “poorly understood,” said RNV Krishna Deepak, who studies snake venom using computational methods at Azim Premji University in Bangalore.

The mechanisms by which these toxins kill human cells are poorly understood, which has hindered progress in developing antitoxins.

To tackle this problem, the researchers first investigated how cobra venom affects human cells. They grew a collection of human cells in the lab. One by one, they removed genes from each member of this collection. (They used CRISPR-Cas9, a Nobel Prize-winning genome-editing tool, to build the collection.) When a gene is knocked out, the cell can no longer manufacture a particular protein.

The researchers then treated the collection with the venom of one of the two snakes and selected for surviving cells. Because this resistance to spitting cobra venom was conferred by the absence of a gene, the authors concluded that the gene is involved in promoting the effect of the venom on normal human cells.

Further investigation revealed that many of these genes are involved in the synthesis of a sugar compound called heparan sulfate, which is known to regulate the formation of blood vessels and blood clots in the human body.

Anticoagulants as antidotes

The researchers hypothesized that if the toxicity of the venom depends on the biological pathway that synthesizes heparan sulfate, then artificially blocking this pathway may reduce the toxic effects of the venom.

One way to do this is to introduce molecules that are similar to heparan sulfate. If the body detects an excess of these molecules, it will shut down the synthesis of heparan sulfate. One such molecule is tinzaparin, a drug used to treat severe blood clots.

When the team administered tinzaparin immediately after exposing the cells to snake venom, the cells survived. Tinzaparin was able to protect these cells even when administered one hour after the cells had been exposed to the venom. Further experiments revealed that tinzaparin works by binding to the venom molecule and blocking the interaction between the venom and its receptors inside the cells.

When the researchers injected mice with either of the two cobra venoms along with tinzaparin, they found that mice that received the drug suffered much less venom-induced skin damage than mice that didn't.

“Hiding close to us”

Dr Deepak, a biologist at Azim Premji University, said the study's use of a “highly efficient CRISPR approach” to an “important but neglected problem” could renew interest among the global scientific community in better understanding the mechanisms underlying snake venom toxicity.

IISc's Dr Sunagar added that the study is “one of the few to consider the molecular mechanisms by which venom causes damage and design a targeted therapy.” The treatment proposed in the study, tinzaparin, is itself cheap, widely available and “lurking right next to us,” Dr Deepak said.

He added that he's excited to see how different research groups follow up on the findings, but he hopes the study will attract enough attention to justify increased funding so that researchers can “use advanced and precise techniques like CRISPR-Cas9 to uncover the molecular mechanisms of snakebite venom.”

Sayantan Dutta is a science journalist and lecturer at Queer University. They tweet at @queersprings.