Potent antivenom for snake neurotoxins developed

Potent antivenom for snake neurotoxins developed

The team examined, among other things, venom from cobras. © designbase / iStock

Snake venom kills thousands of people every year because common antivenoms only have a very specific effect and are not always available. Biomedical scientists have now come a big step closer to the goal of developing a universal antivenom for all snake toxins. They developed a synthetic antibody that neutralizes the toxins of several deadly snakes. Using the same principle, additional antibodies against other snake toxins can now be produced, which together can form a broadly effective and easy-to-produce antidote.

Many snakes use venom to eliminate enemies or capture prey. Up to 138,000 people worldwide die every year from poisoning as a result of a snake bite, especially in African and Asian countries. The antivenoms currently available consist of antibodies that are obtained from the blood of immunized animals and usually only work against a specific snake venom. This technology has been saving lives for decades, but it has serious disadvantages. On the one hand, production in animals is complex and produces antivenoms of variable quality. On the other hand, the antibodies can cause serious side effects in humans and only work in relatively high doses and specifically for only one particular poison.

Looking for antibodies against several toxins

Researchers have therefore long been looking for a simpler and more reliable technique that would produce an antidote with a broader effect against multiple toxins. A team led by Irene Khalek from the Scripps Research Institute in California compared neurotoxins produced by numerous snakes in Africa, Asia and Australia, including elapids such as kraits, cobras and black mambas. Their toxins consist of a mixture of different proteins, including those from the group of so-called long-chain three-finger α-neurotoxins, as the biomedical scientists discovered. These proteins share a specific molecular structure that provides a good target for a “universal” antivenom.

Khalek and her colleagues produced 16 of these toxins in the laboratory in order to examine them more closely. To do this, they developed a screening platform with which they tested 60 billion different synthetic antibodies to see whether they could bind to one or more of these toxins. Such monoclonal antibodies are based on the design of human antibodies and can be produced artificially in the laboratory. This production route is significantly simpler than production in animals and generally provides more tolerable antibodies. The screening revealed almost 4,000 antibodies that bind to one of the snake venoms. 16 of the synthetic antibodies even matched five of these toxins. “We were able to identify the very small percentage of antibodies that reacted with all of these different toxins,” says Khalek. One of these antibodies, called 95Mat5, stood out because it was able to bind particularly strongly to the toxic substances.

First step towards a universal antidote

To further test the effect of this antibody, the researchers used mice to which they administered both 95Mat5 and lethal doses of the various toxins or complete toxin mixtures from the snakes. In fact, this antibody neutralized the neurotoxins in all mice, so that the animals did not die or even show signs of paralysis, as the scientists report. Subsequent structural analysis revealed that the antibody prevents the venom proteins from binding to the receptor known to be responsible for nerve paralysis. This works because the antibody is structurally very similar to the receptor, as the team reports.

“The discovery and development of 95Mat5 is an important first step in the development of a universal monoclonal-based antivenom because it effectively neutralizes one of the most common and toxic components of snake venom,” write Khalek and her colleagues. However, the antibody 95Mat5 does not work against the venom of vipers – the second most important group of venomous snakes – but only against the venom cocktails of the elapids. The biomedical scientists conclude that for a “universal” antivenom against all snake venoms or at least all common classes of toxins, four to five antibodies would probably have to be combined. To do this, they now want to develop and produce three more synthetic antibodies against elapid and viper venoms using the same principle. “We believe that a cocktail of these four antibodies could potentially act as a universal antivenom against any medically relevant snake in the world,” says Khalek.

Source: Irene Khalek (Scripps Research Institute) et al., Science Translational Medicine, doi: 10.1126/scitranslmed.adk1867

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