Snake blood proteins neutralize rattlesnake venom better than current antivenom

Researchers led by Sean Carroll at the University of Maryland have identified a mixture of proteins in the blood of snakes themselves that can block the lethal effects of their own venom. The work builds on a 2022 discovery from Carroll's lab of a single protein called FETUA-3, found in the western diamondback rattlesnake, which blocked many of the metalloproteinase toxins in that snake's venom and also worked against toxins from several other rattlesnake species. The new study tested the individual roles of all the related FETUA proteins, made by co-authors including Elda Sánchez of the National Natural Toxins Research Center at Texas A&M University-Kingsville.

In laboratory tests, combinations of these proteins were about ten times more potent than the current sheep-derived rattlesnake antivenom. The optimized combinations completely neutralized rattlesnake venom lethality and gave broad protection against venoms from multiple viper species, including some separated by millions of years of evolution. A separate summary of the work in Nature describes the result as a mixture of proteins in snake blood that prevented death in mice given an otherwise lethal dose of venom, work that has not been detailed beyond that account here.

Snake venom is not one toxin but a mixture that can contain roughly 100 different toxin proteins spanning multiple protein families, and no two species' venoms are identical. When Carroll's team examined the individual FETUA proteins, they found each had a limited job: one might reduce bleeding, another might affect enzyme activity, but no single protein could fully prevent death from a bite. Combining several of them dramatically increased their ability to neutralize venom's damaging effects, which is why the mixture succeeded where any one protein alone did not.

This is not the only attempt to move antivenom design beyond whole-venom immunization. Earlier work found that an eleven amino acid peptide from opossum blood, an animal known to survive rattlesnake bites, could completely neutralize western diamondback rattlesnake venom in mice when the venom was mixed with the peptide before injection. When that peptide was manufactured in bacteria as a chain of repeated units and then cut apart, the resulting product only partially neutralized the venom in mice, and the authors describe this as preliminary work suggesting a possible therapy rather than a finished one. A separate approach used bioinformatics to scan the genetic sequences active in venom glands and design a synthetic string of DNA carrying seven pieces of one toxin family; antibodies raised against that string in mice neutralized bleeding caused by venom from the carpet viper and a related African viper species.

Snakebites kill an estimated 80,000 to 140,000 people worldwide each year and cause around 400,000 disabilities, according to the Nature summary of the study. Because many people who are bitten live in rural areas, access to antivenom is often insufficient. The antivenom currently approved for pit viper bites in the United States is a treatment made by injecting sheep with venom-derived immunogens and processing the resulting antibody-containing serum, a wholesale vial of which has been reported to cost more than 1,000 US dollars, with immunogenic side effects also reported.

This production method has changed little in over a century. Conventional antivenoms are still generated from the serum of horses or sheep hyperimmunized with whole venom, a mixture of proteins of unknown specificity that requires large injected volumes and raises the risk of allergic and delayed immune reactions in patients. Because venoms vary between and even within species, and their proteins are hard to purify in the quantities needed for immunization, current immunization protocols make no attempt to target only the toxins that matter most clinically.

The current study focused specifically on metalloproteinase toxins, one of several toxin families found in viper venoms. Carroll said the researchers are now applying the same combination strategy to other toxin families, and described the team as "getting remarkably close to having effective solutions for the three major toxin families in vipers." He said this work, together with what has been learned so far, gives him confidence that antivenoms produced in the laboratory using nature-derived protein combinations are within reach, though this remains a stated goal rather than a completed product.

Carroll expects the first commercial applications of this protein mixture to be in veterinary medicine, with human snakebite treatments following later. He also noted an open scientific question: it is not well understood how snakes avoid poisoning themselves with their own venom, even though parts of these protein inhibitors have been conserved across roughly 50 million years of snake evolution. Similarly, the opossum-derived peptide work describes its bacterial-production results as preliminary, and the DNA-immunogen approach against carpet viper toxins was described by its authors as a proof of principle rather than a finished antivenom.