French researchers have found that compounds in one of the world's deadliest snake venoms are as strong as opiates in killing pain, but lack a number of negative side effects.
The next time you come across a Black Mamba, you might want to think twice about your escape – the deadly African snake could be as much of a help as a threat.
French scientists have found that proteins – or peptides – isolated from Black Mamba venom can block pain as effectively as morphine, while at the same time being free of toxic side effects.
The researchers from the Institute of Molecular and Cellular Pharmacology in Valbonne, France, published their study on the venom's painkilling peptides, called mambalgins, in the journal Nature.
In experiments on mice, the peptides bypassed receptors in the brain that are usually targeted by morphine.
The proteins acted on both the central and peripheral nervous systems, stopping pain in a different way from powerful opiates, which can be addictive. But as ever with new drugs, many challenges remain on the path from lab to lips, and it will likely be at least a decade before a drug is publicly available.
Scientists isolated and purified the mambalgins from the venom of the African Black Mamba, which is among the deadliest snakes in the world.
The French researchers injected the compounds into mice and then measured the animals' response to scalding water on their paws and tails.
Mice that had been treated with the snake venom peptides were able to withstand the pain of the hot water for twice as long as untreated ones. The treatment was also effective after repeated dosage - unlike with morphine, to which users typically develop a tolerance.
Eric Lingueglia, a molecular physiologist and head of the research team at the Valbonne institute, says the researchers "were able to identify new channels for the pain pathway."
The mambalgins act on a different pain player than morphine, which until now has been the strongest pain reliever available.
While opiates such as morphine stimulate receptors in the brain, causing pleasure while stopping pain, mambalgins inhibit acid-sensing ion channels, cutting off pain in both neurons of the central nervous system - such as in the spinal cord - and those of the peripheral nervous system, like in the skin.
This also means that the newly discovered compounds are unlikely to cause dependency - a major problem with opiates.
Bryan Grieg Fry, a biochemist and venom expert at the University of Queensland in Australia says this is "the beauty of it - [this painkiller is] not habit-forming."
The mambalgins "block your pain, but don't give you pleasure," says Fry.
In addition to lower drug tolerance and reduced risk of dependency, the mambalgin treatment is also free of other negative opiate side effects, such as constipation and slowed breathing.
"It really has a broad range of potential protective applications," Lingueglia told DW.
But Fry adds that "there are lots of technological difficulties that must be overcome" before a product can be brought to market.
Obstacles to use
One open question is whether the peptide is stable enough to be effective. Lingueglia says he is confident, describing the peptides as "robust," with a "compact structure, usually very resistant to degradation."
Another issue is molecular size. With 57 amino acids, the mambalgins are quite large - perhaps even so big as to provoke an immune response when absorbed, as the body reacts to foreign material.
Fry says the larger molecule structure of mambalgins could "trigger a violent allergic reaction." He thinks the substance will likely have to be made smaller in order for the human immune system to be able to handle it.
Lingueglia concedes that molecule size may be an issue. He says the next step for the drug would be to develop a smaller, synthetic version of the molecule, which would eventually be clinically tested on people.
The isolated peptide has been patented and passed on to a company that will undertake the expensive work of replicating the molecular structure into a practical form. It's also a time-consuming process - Lingueglia says it could take 10 to 15 years for the company to achieve success.
And to develop a non-peptide version that can be taken as a pill, developers of the medication will "need to get in bed with some very, very clever organic chemists," says Fry.
Fry says "millions of years of evolution have made venoms the ultimate smart weapons."
"Neurotoxins smash into the nerves really fast," Fry explains. Their "extreme potency and accurate targeting" makes them well-suited in the search for new painkillers.
Lingueglia says his team had not specifically looked for painkillers, but that they had focused on "identifying new channels in the pain pathway and figuring out how it works." The next step in their research will be to test mambalgins with different pain conditions on mice.
Fry, who has a passion for venomous animals and has worked extensively in the field, describes Black Mambas as "very formidable creatures, among the most dangerous animals" in the world.
"It's surprising," concludes Lingueglia, "to have a very good compound in a very bad venom."