King Kong toxin, a component of the venom in some poisonous marine snails, has a peculiar power to go with its peculiar name.
When injected into a meek little lobster in a tank full of superiors, the poison induces delusions of grandeur; the little guy starts marching around like he's king of the tank. Any given venom can contain hundreds of toxins such as King Kong, including some that are medically useful, but teasing them out of a venom sample is no mean feat. Now, in a methodological breakthrough, researchers at The Rockefeller University have devised a method to speed up this distillation process by orders of magnitude, raising the prospect that they will be able to test a great many of these molecules for their medical potential.
Odd as it may sound, some of the deadliest natural agents in the world have the potential to become among the most beneficial, because their array of peptide components - or toxins - has been refined over hundreds of millions of years of evolution to exquisitely target and manipulate different kinds of cells. "These little creatures that inhabit our planet are masters of developing these bioactive molecules far, far, better than we are," says Brian T. Chait, head of the Laboratory of Mass Spectrometry and Gaseous Ion Chemistry at Rockefeller, where the research was conducted. "It's a huge, largely untapped treasure of beautiful molecules."
The challenge is to break down the tremendously complex venom toxins into their constituent peptides, and then further to identify the exact amino acid sequence of each peptide, so that they can be precisely replicated and tested to discover exactly what they're so good at.
Chait, postdoctoral associate Beatrix Ueberheide, senior research associate David Fenyo and Paul Alewood at the University of Queensland focused on the venom from a single cone snail, a member of Conus textile known as "cloth of gold" for its brilliant shell. "It's a very slow, rather beautiful snail that creeps along and hunts other molluscs," says Chait. "Closely related cone snails hunt fish, and since fish can move in three dimensions very fast, the snails must kill very quickly," Chait says. Their powerful venom, which has killed several humans as well, is shot through a harpoon-like needle that the snail thrusts into the fish. "It's like a lightning strike," says Ueberheide.
Historically, the mission to decode the cone snail's venom peptides has unfortunately proceeded at a snail's pace, with research teams sometimes taking a good portion of a year to find the cipher for a single one. The new method developed at Rockefeller can ratchet that rate by orders of magnitude.
In research published this month by the Proceedings of the National Academy of Sciences , the team revealed the complete amino acid sequence, also known as the de novo sequence, of 31 of the cone snail's peptides, including King Kong toxin, using less than seven percent of their subject's venom. "Until recently, sequencing even a single toxin often required pooling the venom from a number of snails," Chait says.