Tetrodotoxin: Fast way of making pufferfish’s neurotoxin may lead to new pain drugs

Tetrodotoxin, the poison found in pufferfish, is an essential tool for neuroscience research, and a better technique to synthesise it could boost research into drugs that relieve pain

By Alex Wilkins

A quicker way of making one of the world’s most potent neurotoxins could lead to novel drugs for pain relief and to a better understanding of how the body’s pain system works.

Tetrodotoxin (or TTX) is found in some animals, such as pufferfish and sea snails, but is actually made by bacteria. It has a remarkable ability to block sodium ion channels, which nerves use to send signals, and just a few milligrams of it are enough to cause bodily paralysis and death in humans. Sodium ion channels are also essential to how we detect pain, so there is a lot of interest in tetrodotoxin’s potential as a pain-relief drug.

Although TTX is arguably one of the most potent blockers of sodium ion channels, the difficulty in synthesising it has meant that progress in developing drugs by using it has been slow, says Dirk Trauner at New York University.

Now, Trauner and his colleagues have designed a 22-step process that results in 11 per cent of the ingredients used being turned into tetrodotoxin. This is a 10-fold improvement on previous techniques to create it and reduces the number of steps by at least a third.

The synthesis relies on producing a key part of the molecule in a different way. Rather than adding nitrogen-based fragments to the core carbon structure of tetrodotoxin, Trauner and his colleagues add a carbon fragment. Swapping out a carbon-nitrogen bond for a carbon-carbon bond allows them to simplify the entire process, says Trauner.

Tetrodotoxin is used often in neuroscience labs to study how pain works at a cellular level. “It’s virtually an irreplaceable tool,” says Alasdair Gibb at University College London. “It’s one of the most selective and useful tools that people have for neuroscience research. You would find tetrodotoxin in virtually every research lab that was doing cellular neuroscience.”

The discovery of a better way to synthesise tetrodotoxin also opens doors to new avenues of pain research, says Gibb. Researchers will now be able to experiment with slight adjustments to the synthesis process to alter the structure, which could lead to drugs that act differently, and more effectively, on sodium channels in the body.

Both the enhanced yield and reduced number of steps are a huge improvement, says Steve Roome at Hello Bio, a commercial manufacturer of tetrodotoxin. “If that 11 per cent yield is consistent and can be translated to large scales within a manufacturing environment, then I think it would make a fantastic approach for the manufacture of TTX.”

Journal reference: Science, DOI: 10.1126/science.abn0571

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