Researchers have uncovered a natural defense system that helps venomous snakes withstand their own toxins. Credit: Shutterstock

A new study provides a blueprint for the next generation of antivenoms by using snakes’ natural molecular defenses against their own deadly venom.

Venomous snakes carry their own antidotes. Proteins circulating in their blood can block the toxins they produce, protecting the animals from accidental exposure to their own venom.

University of Maryland researchers have now combined several of these natural defenses from western diamondback rattlesnakes. In laboratory testing, specific protein mixtures showed unusually strong neutralizing activity against venom from multiple dangerous snake species.

The research was led by Sean B. Carroll, Distinguished University Professor of Biology, and published in the Proceedings of the National Academy of Sciences. The results offer a possible blueprint for developing more powerful antivenoms for snakebites, which remain a serious health threat in many parts of the world.

“This is one of those great stories when nature has already solved a problem we’ve been grappling with for decades,” said Carroll, who also holds the Andrew and Mary Balo and Nicholas and Susan Simon Endowed Chair at UMD.

Current antivenoms leave major gaps

Snakebites are among the world’s most neglected tropical diseases. The World Health Organization estimates that venomous bites kill between 80,000 and 140,000 people annually and leave hundreds of thousands more with permanent disabilities.

Many of those affected live in rural communities where effective antivenom may be difficult to obtain.

Current antivenoms save lives, but producing them is costly and complicated. Large animals are injected with snake venom, and the antibodies generated by their immune systems are then collected for treatment.

These products can vary in quality and may not work equally well against the wide range of toxins produced by different snake species. They can also trigger serious immune reactions. Seeking an alternative, Carroll and his colleagues looked to the natural protection already present in snake blood.

A western diamondback rattlesnake. Credit: Sean B. Carroll

“We’ve known from anecdotes for 100 years that vipers tend to be resistant to their own venom,” Carroll said. “But for a long time, nobody knew what exactly was circulating in their blood that protected them.”

In 2022, Carroll’s laboratory identified part of the answer. A protein called FETUA-3 blocked the activity of many metalloproteinases, a family of toxins found in western diamondback venom. The same protein also bound to and inhibited toxins from several other rattlesnake venoms.

“Here was evolution’s way for snakes to protect themselves from accidental self-envenomation,” he said, which prompted a follow-up question. “Why rely on horse antibodies when nature has packaged an effective antidote right there in the snake?”

Protein mixtures provide stronger protection

For the latest study, Carroll worked with coauthors including Elda Sánchez, director of the National Natural Toxins Research Center at Texas A&M University-Kingsville, to determine what each FETUA protein contributed.

Individual proteins provided limited protection. One reduced bleeding, while another interfered with toxin enzyme activity. None of the proteins alone completely prevented death following venom exposure.

Combining several FETUA proteins produced a much stronger response, sharply increasing their ability to neutralize venom damage.

Identifying the best mixtures remains difficult. A single venom can contain around 100 toxin proteins from several families, and the exact composition differs among snake species.

“The ingredients are there,” Carroll said. “We just have to keep testing various mixtures.”

In laboratory tests, optimized protein combinations were about 10 times more potent than a current sheep-derived rattlesnake antivenom. They completely neutralized the lethal effects of rattlesnake venom and provided broad protection against venom from several viper species, including some separated by millions of years of evolution.

“The fact that parts of these inhibitors have been perfectly conserved over 50 million years of snake evolution tells you just how real a risk this is for these animals,” Carroll said, noting that how snakes envenomate themselves—whether through mouth tissue during a bite, by eating envenomated prey, through cannibalism or all of the above—isn’t well understood.

Broader antivenoms move closer

The current work concentrated on metalloproteinases. The researchers are now using the same strategy to develop inhibitors for other major families of venom toxins.

“We’re getting remarkably close to having effective solutions for the three major toxin families in vipers,” Carroll said. “What we’ve learned here, together with research we’re doing now, gives us real confidence that nature-based recombinant [lab-produced] antivenoms are within reach.”

Carroll expects that veterinary medicine may provide the first commercial use for this form of “nature’s antivenom,” followed by treatments for human snakebites.

He believes the next generation of antivenoms could protect against a broader range of venoms while being safer, less expensive and easier to produce at large scale than current antibody treatments.

“We could make train cars-worth of this stuff and help solve a massive global health problem,” Carroll said. “Many of our most important medicines have come from nature. I’m delighted that the components for a better-than-commercial antivenom were in these snakes all along.”

Reference: “Nature’s antivenom: Combinations of conserved rattlesnake serum metalloproteinase inhibitors block the lethal action of viper venoms” by Sean B. Carroll, Fiona P. Ukken, Yetunde A. Ayinuola, Luis Escalona, Montamas Suntravat and Elda E. Sanchez, 29 July 2026, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2612168123

This work was funded by the Howard Hughes Medical Institute and the Viper Resource Center (Grant #P40OD01960-22).

Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.