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Venomous drugs: The pressure-drop viper By James Mitchell Crow
The healing powers of toxins In fact, the toxic mixtures of chemicals we call venoms have a long history as medical treatments. From poisonous toads to toxic tarantulas, venomous animals provide ingredients for traditional medicines around the world. Unlikely as it sounds, venoms have many of the attributes a good drug needs. When a venomous animal pounces on its prey, the chemicals it injects must be stable enough to travel around the victim's body and able to evade its defenses until they reach their site of action, when they must hit the target with exquisite selectivity and minimum side effects. Millennia of evolution have honed venoms to achieve exactly what a doctor hopes an injected drug will do. Nevertheless, Western medicine has had difficulties cashing in on this natural asset. In 1981, captopril, a drug based on pit viper venom, became the first venom-derived drug to be approved by the Now, this trickle looks set to turn into a steady stream as venom research enters the genomics age, turning the once-laborious job of sifting through toxic cocktails for potential cures into a high-throughput process. As a result, venom is one of the hottest commodities in pharmaceuticals. New Scientist surveys what it has to offer: 1. DRUG: Captopril SOURCE: Pit viper CONDITION: Hypertension
How does deadly pit viper venom work as a drug? It's all a question of quantity. "Every medicine is also a poison -- the effect depends on the dose," says Pit viper venom provided more than just the original venom-based drug, though. It is also intimately tied up with the discovery of how the body regulates blood pressure. In the late 1960s, this mechanism was still something of a mystery, confounding efforts to manipulate it. Among those working to understand it was The breakthrough came when a Brazilian postdoctoral researcher, During the following decade, the role of ACE in boosting blood pressure by controlling the release of water and salts from the kidneys became clear -- as did the therapeutic value of blocking it. Captopril, a synthetic analogue of the snake venom peptide, was first made in 1975, and hit the clinic just six years later. It was the founder member of what is now a family of ACE inhibitor drugs (Hypertension). Most of the venom-derived drugs approved since captopril also originated in snakes, mainly because snake venoms are the easiest to work with. Compared with a scorpion or a spider, say, snakes produce a vast volume of venom, making them easier to analyze. Snake venom is also a much simpler cocktail than that produced by many other animals: A spider's venom can contain over 1,000 peptides, whereas a snake's venom might contain only 25. 2. DRUG: Chlorotoxin SOURCE: Deathstalker scorpion CONDITION: Cancer Radioactive scorpion venom might sound like the stuff comic-book villains would use. In fact, it's an experimental anti-cancer drug in clinical trials. The venom in question comes from the deathstalker scorpion (Leiurus quinquestriatus), a bright yellow beast native to north Within that sting lies a peptide called chlorotoxin, which has an unusual property -- it sticks strongly to tumor cells while ignoring surrounding healthy tissue, by binding to a cancer-specific protein called matrix metalloproteinase-2. This tumor-targeting makes it a promising ally in the fight against cancer. Load up chlorotoxin with a radioisotope, for example, and it will deliver its radioactive payload straight to a tumor. This approach has been investigated by TransMolecular, a company based in More recently, the peptide has become the key ingredient in an experimental surgical tool called Tumor Paint. When chlorotoxin is tagged with a fluorescent dye, it will illuminate a tumor -- a trick that makes the surgeon's job easier by helping to pinpoint cancerous growth and ensure that all the cancerous cells are removed and healthy tissue spared. Chlorotoxin's performance through the early stages of clinical trials has not gone unnoticed. In "We are reconfiguring the peptide to enhance its utility for diagnosis and treatment of a wide range of cancer types based on the clinical findings of the earlier studies," Cushmore says. 3. DRUG: ShK SOURCE: Sea anemone CONDITION: Autoimmune disease In the warm, shallow waters of the Autoimmune diseases arise when the immune system mistakenly decides that one of the body's own tissues is foreign and begins to attack it. In many cases, the damage is caused by a particular group of immune cells called effector memory T-cells. These possess a unique ion channel called a Kv1.3 potassium channel without which they cannot function, and it is this channel that ShK targets. "ShK puts the cork in the bottle," says Studies in animal models of MS have been a success, and the latest version of the compound is due to start clinical trials in humans by mid-2012. "In MS, there's a lot of nerve damage. We can certainly stop further damage," says Norton. "Time will tell whether we can reverse damage that has already happened -- whether the innate repair mechanisms start to win out once the effector memory T-cells are taken out. We are hopeful." Quite what such a compound is doing in sea anemones in the first place is an open question. Possibly it acts to stun the fish that they eat. Ion channel function can vary significantly from species to species, and the ion channel's role in fish could be very different from its role in our bodies. 4. DRUG: Xen2174 SOURCE: Cone snail CONDITION: Severe pain Divers beware: Not all pretty seashells are harmless. Pick up one containing a live cone snail and it will defend itself with its sting. The result can be fatal. Nevertheless, venom researcher "They're a challenge to get," he says. "During the day they hide, and you can turn hundreds of pieces of dead coral over before you find a cone snail." It's worth the hunt. Cone snails are one of the youngsters of the venom world, developing their poisonous sting just a few tens of millions of years ago. As a result, their venoms are still an evolutionary work in progress. Members of the same species can deploy very different mixtures of chemicals. "Even individuals collected from the same place may only have a 25 percent overlap in the venoms they produce," says Lewis. That means they produce a vast array of potential medicines. Cone snail venom is providing a complementary hunting ground to the more traditional snake venom research. Whereas snake venoms tend to target the cardiovascular system, cone snails prefer to shut down the nervous system of their prey. This means they have great potential as pain medications. One cone snail venom compound discovered by Lewis and his team is about to go into phase II clinical trials. Code-named Xen2174, it works by boosting the signal along the body's natural painkilling nerves that run along the spine. "In our initial safety study, we tested the drug in over 30 people with severe cancer pain, and the compound was able to produce a really quite profound reversal of pain in many of these patients, an effect that could last for many days with a single injection into the spine," says Lewis. Buoyed by their success, the researchers are also starting to develop a painkilling venom-based compound to be given orally. 5. DRUG: Cobratoxin, cobrotoxin SOURCE: Cobra CONDITION: Multiple sclerosis, HIV Snake venom has a place in several ancient medical traditions. As early as the 1930s, Western pharmacists began testing cobra venom as a treatment for conditions ranging from asthma to multiple sclerosis (Expert Opinion on Biological Therapy). But in recent years, modern techniques from mass spectrometry to high-throughput lab-on-a-chip bioassays have made life easier. Chemists can pick out and identify the specific venom components with beneficial effects, eliminating some unpleasant side effects and making the whole process safer. One such component is now showing promise for treating multiple sclerosis. Quite what triggers MS remains unknown. What is clear is that the body's immune system begins to attack the insulating sheath that protects nerve cells, causing damage that can progressively impair sensory and cognitive function and movement. Bringing the immune system back into balance has proved very difficult, but a venom peptide called cobratoxin might hold the answer. Last year, Meanwhile, a related venomous molecule called cobrotoxin has shown promise in treating HIV. A modified version of the toxin seems to impede the spread of the virus by blocking receptors on the surface of the body's immune cells - the same receptors that the virus would otherwise latch on to before infecting the body's immune cells. 6. DRUG: Exenatide (Byetta) SOURCE: Gila monster CONDITION: Type 2 diabetes A bite from a gila monster will really mess with your metabolism. Fortunately, these lizards, found in the deserts of the southwestern U.S., are large and lumbering and most humans can easily outpace them. Nevertheless, each year a handful of people do get close enough to discover that the gila monster's bite delivers a painful cocktail of chemicals that causes nausea, fever and faintness -- and can even induce a heart attack. However, within the venom lies a very useful compound. Called exendin 4, it triggers one of the body's insulin-releasing pathways. This effect makes it ideal for treating type 2 diabetes, a condition in which insufficient insulin is produced to keep glucose levels in check. A synthetic version of exendin 4, called exenatide, was approved as an anti-diabetes drug by the Until around five years ago, the gila monster was thought to be one of just two venomous lizards -- the other being the closely related beaded lizard found in nearby Research into lizard venom has barely begun, so it may be a while before any other lizard-based medicine hits the pharmacy. But the wait could be worth it, says "If you want to find something useful, then the more novel the venomous animal, the more novel its venom," says Fry. And that gives the best drug leads, he notes. "I think it's one of the strongest arguments we have for preserving biodiversity."
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