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Predatory marine cone snails are common in tropical seas where they prey on small fish and other aquatic life using poisonous stings, which can also be fatal to humans. Their venom contains a cocktail of toxins, among which molecules known as peptides – or mini-proteins – are common.
Cell biologists have studied these conopeptides because of their important effects on the human nervous system. They are already used in neuroscience research and drug development, with a medication for the treatment of severe pain approved by US regulators.
However, although cone snail venom contains some 200 000 promising bioactive compounds, related research is complicated because conopeptides are difficult to obtain or synthesise chemically.
The EU-funded CONBIOS project discovered a better method for producing conopeptides, offering the prospect of new pain relief drugs for millions. CONBIOS also found new insulin molecules that reduce sugar levels much more quickly than current diabetes drugs. Both these important discoveries received international media attention.
“The poor availability of conopeptides has been a bottleneck for researchers for decades,” says project coordinator Lars Ellgaard of the University of Copenhagen in Denmark. “Rather than seeking chemical solutions we went back to the snail itself and studied how it manufactures conopeptides effectively in its venom glands – and we discovered more than we expected.”
Properly folded peptides
Synthesising conopeptides is difficult because when the linear peptide molecule is formed it then needs to ‘fold’ into a three-dimensional shape to be effective. This process often goes wrong during chemical synthesis in a test tube, resulting in very low yields.
CONBIOS carried out extensive research on cone snail venom glands and discovered specialised enzymes that help newly-formed conopeptide molecules fold properly.
“We found that these enzymes significantly accelerated folding of conopeptide molecules,” says Ellgaard. “When we then produced these enzymes in a bacterium together with linear conopeptides in a laboratory-scale system, we found high yields of correctly folded conopeptides.”
Helena Safavi-Hemami, who worked on CONBIOS as the recipient of an EU Marie Skłodowska-Curie fellowship, highlighted how conopeptides are used extensively as a research tool in neurobiology because they are so specific in their behaviour.
“Conopeptides can distinguish between similar target molecules and bind to them selectively,” she says. “For example, they can be used to block the activity of a specific molecule allowing us to observe the results and understand its function in the body.”
There are also important therapeutic uses.
“Chronic neuropathic pain, such as from spinal cord injuries or cancers, is difficult to treat; often relying on morphine as a last resort,” Safavi-Hemami says. “More targeted pain relief based on conopeptides is becoming available and, with more conopeptide accessible for research and development, we can expect more and better treatments for these debilitating conditions.”
Unexpected diabetes discovery
While investigating the rich cocktail of molecules in cone snail venom, the researchers found something surprising – a form of insulin that is unlike snail insulin but shares features with fish and human insulin.
Insulin had never been found in any animal venom before. Experiments confirmed that it was used to overload fish prey with insulin, causing hypoglycaemic shock and immobilising the fish to allow their capture.
“Even more surprising is that while these insulin molecules are the smallest known in nature, they are extremely fast-acting in reducing sugar levels,” says Safavi-Hemami. “Current fast-acting insulins can lower sugar levels within an hour or so in humans, cone snail insulin can act within minutes. If human insulin can be tweaked to resemble snail insulin then this would be a breakthrough for diabetes sufferers.”
CONBIOS showed how there is always more to learn from nature, concludes Ellgaard.
“We managed two for the price of one in CONBIOS – both the folding enzymes and the venom insulin,” he says.
CONBIOS received funding through the EU’s Marie Skłodowska-Curie fellowship programme.