AI-Designed Proteins Revolutionize Antivenom Treatment

Scientists are harnessing AI to develop innovative proteins that counteract deadly snake venom toxins. These proteins could transform snakebite treatments worldwide and save countless lives in regions where snakebites are a critical public health issue.

Research: De novo designed proteins neutralize lethal snake venom toxins. Image Credit: hecke61 / Shutterstock

New proteins not found in nature have been designed to counteract certain highly poisonous components of snake venom. The deep learning computational methods for developing these toxin-neutralizing proteins offer hope for creating safer, more cost-effective, and more readily available therapeutics than those currently in use.

Each year, more than 2 million people suffer from snakebites. More than 100,000 of them die, according to the World Health Organization, and 300,000 suffer severe complications and lasting disability from limb deformity, amputation, or other aftereffects. Sub-Saharan Africa, South Asia, Papua New Guinea, and Latin America are among the places where poisonous snakebites pose the most significant public health concern.

The computational biology effort to discover better antivenom therapeutics, led by scientists at the UW Medicine Institute for Protein Design and the Technical University of Denmark, is reported in Nature today, Jan. 15. 

Susana Vazquez Torres, the paper's lead author, is from the Department of Biochemistry at the UW School of Medicine and the UW Graduate Program in Biological Physics. She lives in Querétaro, Mexico, near viper and rattlesnake habitats. Her professional goal is to invent new drugs for neglected diseases and injuries, including snakebites.

Her research team, including international experts in snakebite research, drugs, diagnostics, and tropical medicine from the United Kingdom and Denmark, focused on finding ways to neutralize venom gathered from certain elapids. Elapids are a large group of poisonous snakes, among them cobras and mambas, that live in the tropics and subtropics. 

Most elapid species have two small fangs shaped like shallow needles. During a tenacious bite, the fangs can inject venom from glands at the back of the snake's jaw. Among the venom's components are potentially lethal three-finger toxins. These chemicals damage bodily tissues by killing cells. More seriously, by interrupting signals between nerves and muscles, three-finger toxins can cause paralysis and death.

Presently, venomous snakebites from elapids are treated with antibodies taken from the plasma of animals immunized against the snake toxin. Producing the antibodies is costly, and they have limited effectiveness against three-finger toxins. This treatment can also have serious side effects, including causing the patient to go into shock or respiratory distress.

"Efforts to try to develop new drugs have been slow and laborious," noted Vazquez Torres. 

The researchers used deep learning computational methods to speed the discovery of better treatments. By binding with them, they created new proteins that bind to the three-finger toxin chemicals and interfere with their neurotoxic and cell-destroying properties. 

Through experimental screening, the scientists obtained designs that generated proteins with thermal stability and high binding affinity. The actual synthesized proteins were almost a complete match at the atomic level with the deep-learning computer design.

In lab dishes, the designed proteins effectively neutralized all three of the subfamilies of the three-finger toxins tested. When given to mice, the designed proteins protected the animals from what could have been a lethal neurotoxin exposure.

Designed proteins have key advantages. They can be manufactured with consistent quality through recombinant DNA technologies instead of by immunizing animals. (In this case, recombinant DNA technologies refer to scientists' lab methods to synthesize a computationally designed blueprint for a new protein.)

Also, the new proteins designed against snake toxins are smaller than antibodies. Their smaller size might allow them to penetrate more deeply into tissues, quickly counteracting the toxins and reducing damage.

In addition to opening new avenues for developing antivenoms, the researchers think computational design methods could be used to develop other antidotes. Such techniques might also be used to discover medications for undertreated illnesses that affect countries with significantly limited scientific research resources. 

"Computational design methodology could substantially reduce the costs and resource requirements for development of therapies for neglected tropical diseases," the researchers noted. 

The senior researchers on the project to design protein treatments for elapid snakebites were Timothy J. Perkins at the Technical University of Denmark and David Baker of the UW Medicine Institute for Protein Design and the Howard Hughes Medical Institute. Baker is a professor of biochemistry at the UW School of Medicine.

The University of Washington has submitted a provisional U.S. patent application for the design and composition of the proteins created in this study.