Bullfrog Protein Saxiphilin Acts as Effective Antidote for Marine Saxitoxin

The "red tide" algal blooms that are becoming more frequent along the Pacific coast produce one of the most potent neurotoxins known: saxitoxin, or STX. The toxin accumulates in shellfish and causes paralytic shellfish poisoning (PSP) when consumed.

There is no antidote for STX, which was stockpiled as a chemical weapon during the Cold War. But a new UC San Francisco study is likely to change that. 

In research published July 16 in Nature Communications, a team led by Daniel Minor, PhD, professor in UCSF's Cardiovascular Research Institute, found that a protein called saxiphilin can neutralize saxitoxin in mice, preventing and even reversing otherwise lethal poisoning.

The protein, which occurs naturally in bullfrogs and other frogs from around the world, acts like a molecular sponge. It binds tightly to saxitoxin in the bloodstream before the toxin can reach the nerve and muscle cells it normally attacks.

Earlier efforts to find an antidote against the toxin focused on interrupting the complex biological processes it uses to disable nerve cells or trying to trigger immune responses against it. Those approaches have been largely unsuccessful.

This was a problem looking for a solution. It turns out that one naturally occurring protein is all that's required to take this toxin out of commission."

Daniel Minor, Professor, University of California, San Francisco

With harmful algal blooms becoming more frequent worldwide, the discovery could have important public health implications. Minor's approach, developed in collaboration with Stanford chemist Justin Du Bois, PhD, may also guide researchers to antidotes for other naturally occurring toxins found in harmful algal blooms.

Testing a Toxin "Sponge"

The current study builds on a 2021 paper in which Minor and colleagues showed that saxiphilin binds strongly to saxitoxin, essentially soaking it up like a sponge and blocking its toxic properties. But whether that interaction would work inside a living organism remained uncertain.

To find out, Minor and postdoctoral scholars Samantha Nixon, PhD and Sandra Zakrzewska, PhD, tested saxiphilin in mice exposed to lethal doses of STX. When saxiphilin was given before or along with STX, the protein prevented poisoning. It also cured nearly all mice who got the protein after they were exposed to STX a scenario that most closely resembles what would occur when someone unknowingly eats poisoned shellfish. 

Minor said this latter scenario was particularly encouraging, given the size of the antidote molecule, which the researchers thought might slow down its action. 

"We had this really big protein that needed to catch up with a tiny toxin molecule that has a running start on it," Minor said. "We really weren't sure this was going to work."

The protein not only improved survival but also reduced symptoms associated with severe poisoning, with no harmful side effects.

The team also discovered that saxiphilin spread throughout the body, reaching the brain, heart, and muscles, allowing it to intercept the toxin wherever it traveled.

Closing a Century-Old Scientific Circle

The discovery has roots in UCSF research dating to the late 1920s and 1930s, when Hermann Sommer, MD, a physician-scientist at the George Williams Hooper Foundation for Medical Research at UCSF investigated shellfish poisoning outbreaks along the California coast.

Sommer showed that what was then called "mussel poison" originated not in shellfish themselves but from microorganisms associated with them. His work helped lay the foundation for the eventual identification of saxitoxin. He also observed that certain frogs appeared resistant to the toxin. Nearly a century later, that observation has been proved correct.

It is now known that there STX is not a single toxin but a family of over 50 variants with closely related structures. In two studies, published in 2025 and 2026, Minor showed that saxiphilin can bind a wide range of these variants, making it a good candidate for an antidote.

His next goal is to determine whether smaller, engineered versions of saxiphilin could provide the same, or maybe even better, protection against an array of STX variants.

The research could also improve how public health officials monitor shellfish safety. California's state testing laboratory in Richmond routinely screens shellfish for paralytic shellfish toxins, and Minor hopes saxiphilin eventually could serve as a highly sensitive detection molecule that makes testing faster and simpler.

More broadly, he believes the work offers a blueprint for finding antidotes to many other natural toxins that currently have none.

"Nature has had to solve this problem multiple times," he said. "So, there is resilience to toxins all over the biological world."