Venom with a positive punch

Thu, Feb 23, 2012, 00:00

Some of nature’s deadliest substances are proving to be unusual sources for beneficial drugs and therapies

FROM PAINFUL BEE stings to poisonous jellyfish, deadly snake bites to killer cone snails, an encounter with venom is best avoided. Yet it turns out that venom has an upside: it’s a useful place to go looking for natural molecules that can act as or inspire new drug therapies.

Venoms are packed with bioactive molecules that are like “smart weapons”, explains Chris Shaw, professor of drug discovery at Queen’s University Belfast’s school of pharmacy.

“Venoms have been around for a long time. By and large they are used in nature for subduing, killing, capturing prey or for defensive purposes,” he says. “These are designer molecules – they have been honed to perfection in hundreds of millions of years of natural selection out there in the great war of survival.”

At first glance, it might not seem intuitive to go poking around nasty toxins to hunt for medicines, but , as Shaw points out, even prescription medicines can be dangerous at the wrong dose. “All these medicines are poisons and toxins,” he says. “We tame them and use them at sub-lethal doses where they have a therapeutic effect.”

Venoms have already shown good form in turning up new drugs for human use. A widely used class of blood-pressure-lowering medication called ACE inhibitors got its lead from the venom of a Brazilian pit viper, while a drug used to treat diabetes called exenatide is a synthetic version of a molecule in the venom of the Gila monster lizard.

Another venomous gem is chlorotoxin, from a scorpion species, which has a talent for targeting cancer cells. So there’s plenty of reason to go sifting through venom for more leads on useful therapeutic drugs: but how do you get the starting material?

“We have developed our technology so we can look at protein, DNA and mRNA without killing anything,” says Shaw. “We take our venoms and amphibian skin secretions totally non-invasively, it doesn’t hurt the animal, and we can do these things in the field or in the lab.”

His own group has seen recent success isolating two small peptides – one from a South American tree frog and one from the skin of a Chinese toad – that could ultimately be of clinical use.

“One stops blood vessels growing, so we are looking for applications in cancer treatment and wet macular degeneration, where you go blind because you get a lot of new blood vessels growing behind the eye,” says Shaw.

“The other was the opposite, a pro-angiogenic, it makes blood vessels proliferate – so it could [potentially] be used for wound healing, transplant surgery, cosmetic surgery, scar healing.”

The lab is looking for leads in reptiles and scorpions too, and again finding interesting agents, according to Shaw.

Another success story was the discovery of powerful dendrotoxins in the venom of mamba snakes. Prof Alan Harvey recalls how he and collaborators started working on the African snake venom around three decades ago.

“We did some very simple experiments and I predicted a very boring outcome but I was completely wrong,” recalls Harvey, who was in the University of Strathclyde in Glasgow at that time.

“[We] had an experimental preparation that had a muscle and nerve attached to it, and we expected it to be blocked. But what happened was that the muscle started to contract better than ever – at that point, we knew we had found something interesting.”

It turned out that toxins in the mamba venom were blocking a particular ion channel that lets potassium flow out of the cells. The highly specific nature of the toxins has since provided a useful experimental tool to help scientists unpick physiological processes.

“It has been very hard to design highly selective classical small molecular weight drugs to block potassium channels,” says Harvey. “And molecular biology shows there’s a rich repertoire of potassium ion channels, especially in the nervous system – people are trying to work out the contribution of one channel compared to another in signalling and rhythmic patterns of nerves.”

Harvey, who earlier this year moved to Dublin City University as vice-president for research and innovation, was also involved in the five-year European Conco project to look at venom from a cone snail. It’s a small animal, but the marine snail Conus consors has an intriguing hunting strategy.

“Snails in the sea are not any faster than the snails you get in your garden, and fish are pretty fast,” says Harvey. “So the cone snail sits a little bit buried in the sand in the seabed and it attracts the fish. When the fish comes close enough the fish-hunting snail can expel a harpoon-like disposable tooth – it has a barb on the end and is hollow, like a hypodermic syringe, and the end of it is connected to a venom sac. The snail harpoons the fish, and pumps venom down the tube.

“These venoms are a cocktail of toxins that act at different times – individually they probably would kill a fish but they would take maybe 10 minutes, yet when they are all together they can paralyse the fish in a matter of seconds.”

Cone-snail venom had previously yielded molecules which are useful in pain relief, and the Conco project has now found a sodium ion channel blocker that has long-lasting effects.

The cone-snail analysis could have more to offer, according to Harvey: “There are quite a few intriguing findings that are still being investigated,” he says.

QUB’s Chris Shaw also paints a picture of a field with many possibilities. Hunting for natural products in venom is an area that he says is on the up: “I think they are about to come into their own.”

Sifting through a molecular bin

When a mammalian cell is faced with a nasty or dangerous molecule, it often sends it to the “bin”: a section in the cell called the lysosome where molecules get smashed up and recycled.

But some toxins seem to get around this security measure, and a project at University College Dublin is looking to figure out why. The hope is that what they identify could help find new ways to deliver therapeutic drugs or nanoparticles into cells more effectively.

Dangerous molecules, such as ricin (a poison that was infamously injected into Georgi Ivanov Markov from an umbrella tip) and the agents in the bacteria Shigella and E coli that give us food poisoning, have ways to avoid that route to the cellular bin, says Jeremy Simpson, professor of cell biology at UCD. Instead, they seem to get moved into cells in a way that means they can remain active.

“The premise we are working on is that if we could understand how these toxins traffic through these pathways, then we could apply this knowledge in the drug delivery context,” says Simpson.

Plans are underway to individually knock down around 22,000 genes in human cells growing in the lab, and use an automated system to look at what subsequently happens when a safe version of an E coli toxin or else artificial nanoparticles are trafficked into cells.

“We will do all all 22,000 genes systematically,” says Prof Simpson. “Once we have got a list of genes associated with these pathways we can hopefully be a bit more intelligent about understanding which genes and proteins are responsible for how these things go inside cells. And the main driver for what we would like to do, is to use this knowledge to improve drug delivery.”