High-tech antidotes for snake bites

THE BITEAIIISIISAIDNAAIDNA of a black mamba (pictured) causes respiratory muscular paralysis. And death. Disturb a Russell’s viper and the encounter may lead to kidney damage and excess bleeding. And death. As to the , well, you get the idea.Whatever the assailant, though, snake-bite treatment has been the same for a century: inject an antivenin containing antibodies produced in a horse or sheep. Doctors would love to replace this antiquated, batch-based approach, with its risk of provoking allergic reactions, with one that yields an allergen-free product cheaply and in quantity. Early results from two groups, one working in old-fashioned wet labs and the other using new-fangled artificial intelligence (), look promising.The wet-labbers are based at Scripps Research in San Diego, the Indian Institute of Science () in Bengaluru and the Liverpool School of Tropical Medicine. The problem they are trying to overcome, according to Kartik Sunagar of the , is the multiplicity of venom types, both within and between species of snake. To simplify things, they are concentrating initially on a group of molecules called long-chain three-finger alpha-neurotoxins. These are important parts of the armamentaria of the elapids, a group of snakes that includes mambas.The track is led by David Baker of the University of Washington, winner of a share of the 2024 Nobel chemistry prize for his work on computational protein design. He and his colleagues also have long-chain three-finger alpha-neurotoxins in their sights. Both groups are looking for proteins able to neutralise a range of types of the target alpha-neurotoxins—molecules that are, themselves, proteins—by binding to them and thus rendering them ineffective.As they describe in a paper published last year in , the wet-lab team is trying to supercharge antibodies—or immunoglobulins, as they are known to molecular biologists—and also cut out the use of animals. (Existing antivenins are created by the messy process of injecting snake venom into the chosen animal to provoke an immune response, and then extracting the resulting antibodies from the animal’s blood serum.)The amino-acid chains of an immunoglobulin include “hypervariable” regions where the sequence of amino acids differs from protein to protein. Different sequences bind to different targets, and a huge number of sequences is possible—theoretically, up to a billion billion. Moreover, it is easy to generate large numbers of different immunoglobulins, or fragments thereof, in a laboratory, by inserting the relevant into yeast cells.To find the right candidate, the team screened billions of antibody fragments, expressed on the surfaces of these genetically modified yeasts, against eight representative alpha-neurotoxins. They then injected groups of mice with the winner and with venom from one of three types of elapid: black mambas, many-banded kraits and monocellate cobras. All survived.Professor Baker’s approach, just published in, ignored immunoglobulins in favour of entirely new types of protein molecule, designed from scratch. His first calculated what shape a protein would need to be to fit snugly into the toxin’s active site (the place that binds to its target). In this he was helped by the fact that, though alpha-neurotoxin molecules vary a lot in their peripheries, their active sites are similar. A second program then worked out which amino acids, and in what order, would be needed to make such optimal proteins, coming up with multiple answers to this question. A third then assessed whether the amino-acid chains thus lit upon really would fold into the desired shape, and thus might do the job.Only at this point, having picked the most plausible candidates, did the team actually do experiments. They synthesised pieces of that encoded the most promising designs, inserted them into yeast, churned out the relevant proteins, and tested them against venom samples. They then picked the most successful of these and injected them into mice. Depending on the dose, the toxin and the protein being tested, between 80% and 100% of the mice survived.How all this will play out in people remains to be seen. Much work remains if these discoveries are to be turned into actual medicines. But if that does happen, human casualties from snake bites, which cause around 100,000 deaths a year and thrice that number of disabilities, may significantly diminish.