A recipe for deadly poison dart frog toxin

Poison dart frogs pack a powerful poison punch. And for the first time, chemists have synthesised the toxin along with its molecular mirror image  – and found the reversed form of the poison has the opposite effect on cells.

The recipe was published in Science by Matthew Logan from Stanford University in the US and colleagues.

It’s “tremendously important” work that could lead to medicines, according to Bryan Fry from the University of Queensland in Australia who was not involved in the study, “not only because of the new knowledge it will give us immediately that we can build on, but also because these are very small molecules of the kind that can be absorbed.

“This is why frogs use it as part of their poisonous defence.”

Poison dart frogs might look like cute colourful little toys, but don’t be fooled. Their toxin, called batrachotoxin, forces open sodium channels on nerve cell membranes – with horrific results.

The influx of sodium into a nerve cell means it fires, but because batrachotoxin stops sodium channels from closing, the cell can’t switch “off” again – causing paralysis, cardiac arrest and even death.

These toxins are handy in the lab, though. They tell physiologists about the channels they clamp to.

You can think of a sodium channel like a lock, says Fry. If you want to find out information about the lock, you can try different keys.

The structure of the keys that do open the lock tell you information about the structure of the lock itself.

And there’s plenty to be learnt from batrachotoxin – but getting some is not a simple task.

In 1963, scientists trekked through the northern rainforest of Colombia to collect the first portion of this toxin from poisonous frogs from the genus Phyllobates.

Today, poison dart frogs are endangered and collecting natural batrachotoxin is restricted. It can be found in some species of birds and beetles, but in amounts so small it is hardly worthwhile.

So, knowing how useful it could be, Logan and his colleagues set out to create a synthetic version.

And while they successfully synthesised batrachotoxin in 24 steps, they also prepared the unnatural, mirror image form of the molecule.

Some molecules have two forms – a left-handed and right-handed form. These molecules are called “chiral”.

Each form of the same molecule can have different effects. Most famously, one form of the drug thalidomide helped women with morning sickness. Its mirror image, though, caused birth defects.

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Molecular model of batrachotoxin (left) and its chiral mirror-image (right). Carbon is grey, hydrogen is white, nitrogen is blue and oxygen is red.

So Logan and his crew wondered if the mirror-image form of batrachotoxin (which isn’t found in nature) might also bind to sodium channels – and if so, with what effect.

Lo and behold, testing revealed that the two toxins have completely different effects on cells.

The mirror image blocks sodium ion channels rather than keeping them open – and unlike the natural deadly form, the block could be removed and the cells go back to normal.

Playing around with different forms of these molecules allows them to explore even more about the channel function – and exploiting the differences often generates medical treatments – maybe an antidote to the deadly natural form of batrachotoxin.

Fry says the researchers are already “ahead of the curve.

“Because these are very small molecules, and of the size that can be absorbed, if [researchers] come up with a useful activity, then it’s already the right kind of molecule that can be made into a medicine. “

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