Proteins from the black mamba could inspire painkilling drugs
With a series of swift bites, the black mamba snake injects a toxic cocktail that can kill a person within 20 minutes. But among the mix of compounds that squirt from the animal’s fangs, two proteins can block pain in mice as effectively as morphine — and with fewer side effects, according to a study published today in Nature1.
The snake proteins — called mambalgins — represent the latest find as scientists search for alternatives to morphine and other opiate drugs. Many patients grow tolerant to opiates, requiring higher doses over time, while others suffer from side effects such as nausea, constipation, and drug dependency.
“It’s important to try to develop new drugs that can have complementary or different types of action,” says Eric Lingueglia, a molecular physiologist at the Institut de Pharmacologie Moleculaire et Cellulaire in Valbonne, France. He and his colleagues identified the mamba snake proteins after testing about 50 different animal venoms.
The team found that mice injected with mambalgins could withstand hot water on their tails and paws for about twice as long as untreated animals. The snake proteins also reduced hypersensitivity to pain following tissue inflammation. Over 5 days of repeated treatment the mice developed a tolerance for both opiates and mambalgins, but the effect was less pronounced with the snake venom proteins.
Instead of acting on opioid receptors like morphine, mambalgins bind and inhibit molecules in the family of acid-sensing ion channels, or ASICs. The ion channels, which form pores in neuronal membranes, have been implicated in pain transmission, but their precise role remains poorly understood.
Mambalgins inhibited different subtypes of ASICs when injected in the mouse brain and spinal cord, and or when injected in the paw, suggesting multiple potential targets for future drug development, says Lingueglia.
He hopes that mambalgins or related molecules will become clinically viable, but many steps remain. “This study is done in mice, so the first thing to do is make sure it’s the same as in humans,” he says. Initial tests suggest mambalgins block some human ASICs in vitro.
Power in poison
At least one other venom-based painkiller is commercially available, which mimics the venom of cone snails. Venom proteins from sea anemones, spiders, and scorpions have also been found with potential biomedical uses2.
Richard Lewis, who studies venom therapeutics at the University of Queensland in Brisbane, Australia, says the finding is “exciting". “There’s been very few new drugs to come out to treat pain in the last 10-15 years, and very few new modes of action,” he says.
“It’s nice they’ve gone the extra mile to show that the side effects there are with opiates like morphine aren’t there,” adds Laura Bohn, a pharmacologist at the Scripps Research Institute in Jupiter, Florida. However, she notes that more work is needed to analyse how the snake proteins travel through the body and break down into byproducts.
David Julius, a physiologist at the University of California, San Francisco, has studied other snake venom proteins that activate ASICs3. He says the snakes are a valuable source of new molecules. “These venom sacs are basically evolving combinatorial peptide libraries. There’s some stuff in there that the animal can use,” says Julius, and some “that just turns out to be useful for us”.
Diochot, S. et al. Nature. doi:10.1038/nature11494 (2012).
Lewis, R. J., Garcia, M. L. Nat. Rev. Drug Discov. 2, 790-802 (2003).
Bohlen, C. J. et al. Nature. 479, 410–414 (2011).
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Shen, H. Deadly snake venom delivers pain relief. Nature (2012). https://doi.org/10.1038/nature.2012.11526