In this 21st Century Chemist profile, City University of New York chemist Mande Holford explains her research on the toxins produced by venomous sea snails, and her work to synthesize these long-peptide toxins for eventual use in treating chronic pain in humans.
Chemistry of Biotoxins - Using Venom from Deadly Snails to Kill Pain
TOM COSTELLO, reporting:
They're small, slow, and lethal. Venomous sea snails, found in warm waters around the world, carry enough toxin to kill a human in a matter of minutes. But incredibly, these underwater predators, and the toxins they produce, are helping scientists make breakthrough discoveries in treating chronic pain in humans.
MANDE HOLFORD, (Peptide Chemist, CUNY, AMNH): Normally, when you think of venomous things, you think of snakes or spiders or scorpions. But these marine snails or sea snails that we work with, the toxins that they produce in their venom. We found that they are very useful as potential therapeutics.
COSTELLO: Mande Holford, an assistant professor at City University of New York who’s funded by the National Science Foundation, studies how toxins found in sea snails interact with the human central nervous system. Holford studies two species of venomous sea snails called terebrids and turrids, which she collects from field sites around the world.
HOLFORD: These are turrids that we collected in Panama.
COSTELLO: Terebrids and turrids can produce anywhere from 50 to 200 different toxins. These toxins affect how pain receptors, called neurons, communicate in the nervous system.
HOLFORD: If I pinch your finger you'll say ouch and it's because there is a neuron signaling to another neuron to tell your brain move away, this is hurting. And so that sort of what the toxins do. They either propagate that signal meaning have it move faster or they inhibit it.
COSTELLO: In the body, nerves transmit signals using electrical impulses. These impulses are controlled by the movement of positively charged particles called ions between the interior and the exterior of the nerve cell. Specialized ion channels regulate the movement of ions between nerve cells. These ion channel act like 'gates,' preventing or permitting the flow of ions through the cell. Holford is studying how terebrid and turrid toxins affect the sodium gates.
HOLFORD: The channels dictate how those ions move. And so the toxins work either to block the gate so that sodium ions don't move back and forth across the neuron membrane or they are inactivated so that it's sort of stuck-open.
COSTELLO: Whether an ion channel is blocked or stuck-open determines whether nerve impulses will continue traveling through the body. But only a small amount of toxin can be collected from the venom gland of each snail, so Holford is engineering synthetic versions of these naturally occurring toxins, a process she calls solid phase peptide synthesis. Picture a string of beads with each bead representing a different amino acid -- the chemical building blocks that make up proteins. In a peptide toxin, individual amino acid "beads" are arranged in a specific sequence. This sequence determines how each peptide toxin will function in the nervous system. Holford makes a synthetic version by building a sequence of amino acid beads, onto a polystyrene support.
HOLFORD: It's basically building that bead-on-the-string literally until you have all of the full compliment of amino acids necessary for a particular peptide.
COSTELLO: But the problem with peptide toxins is that they are made up of long chains of amino acids. Holford is trying to build smaller, shorter sequences of amino acids, which would make them cheaper and easier to manufacture.
HOLFORD: The major drawback with the toxins is that it's the size. So morphine is a small compound, these toxins range between ten to forty or even sixty amino acids long. And so that's not a size that's conducive for drug development. You have to make something of a lot smaller because it's easier to synthesize.
COSTELLO: Scientists have already created a painkiller derived from another type of cone snail called Ziconotide, the generic name for the drug Prialt. Holford hopes for a similar breakthrough with her own snail species, which humans have both feared and marveled at for centuries.
HOLFORD: These are beautiful organisms. They've been collected for hundreds and thousands of years. Nature has shown us that there's this wonderful beautiful shell but it also has now some scientific relevance. And so in terms of just learning about what's here on the planet with us these creatures are wonderful to study.
Snake venom is the poisonous, typically yellow fluid stored in the modified salivary glands of venomous snakes. There are hundreds of venomous snake species that rely on the venom they produce to debilitate and immobilize their prey.
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