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Venomous drugs: Chlorotoxin
left alamy,right Matt Reinbold
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 Bryan Fry, who researches venomous animals and their evolution at the University of Queensland in Brisbane, Australia. “The snake kills by dropping its target’s blood pressure through the floor,” he says. “To use the venom as a drug, you just give less of it.” 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 John Vane, a pharmacologist at the Royal College of Surgeons of England. The breakthrough came when a Brazilian postdoctoral researcher, Sérgio Ferreira, joined Vane’s group. Ferreira had been studying the venom of a pit viper native to Brazil, Bothrops jararaca, and he brought a sample of it with him. The team discovered that a toxic peptide in the venom would selectively inhibit the action of angiotensin-converting enzyme (ACE), a chemical suspected of playing a role in the regulation of blood pressure. 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, vol 17, p 589). 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 analyse. Snake venom is also a much simpler cocktail than that produced by many other animals: a spider’s venom can contain over 1000 peptides, whereas a snake’s venom might contain only 25.
The deathstalker scorpion is helping in the fight against cancer
DRUG: Chlorotoxin SOURCE: Deathstalker scorpion CONDITION: Cancer Radioactive scorpion venom might sound like the stuff comic-book villains would use. In fact it is 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 Africa and the Middle East. As the name suggests, its sting can be fatal. Within that sting lies a peptide called chlorotoxin, which has an unusual property – it sticks strongly to tumour cells while ignoring surrounding healthy tissue, by binding to a cancer-specific protein called matrix metalloproteinase-2. This tumourtargeting 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 tumour. This approach has been investigated by TransMolecular, a company based in Cambridge,
Massachusetts, as a way to treat glioma, a form of brain cancer. Chlorotoxin passed a phase II clinical trial in 2009. 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 tumour – 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 April 2011, TransMolecular’s tumour-targeter was snapped up by biopharmaceutical company Morphotek, a US-based subsidiary of Japanese drug giant Eisai. Though the company will not go into the details of its plans for chlorotoxin, spokesman Terry Cushmore says they intend to refine it before taking it into further clinical studies. “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,” he says. > 5 May 2012 | NewScientist | 35
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 Bryan Fry, who researches venomous animals and their evolution at the University of Queensland in Brisbane, Australia. “The snake kills by dropping its target’s blood pressure through the floor,” he says. “To use the venom as a drug, you just give less of it.” 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 John Vane, a pharmacologist at the Royal College of Surgeons of England. The breakthrough came when a Brazilian postdoctoral researcher, Sérgio Ferreira, joined Vane’s group. Ferreira had been studying the venom of a pit viper native to Brazil, Bothrops jararaca, and he brought a sample of it with him. The team discovered that a toxic peptide in the venom would selectively inhibit the action of angiotensin-converting enzyme (ACE), a chemical suspected of playing a role in the regulation of blood pressure. 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, vol 17, p 589). 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 analyse. Snake venom is also a much simpler cocktail than that produced by many other animals: a spider’s venom can contain over 1000 peptides, whereas a snake’s venom might contain only 25.
The deathstalker scorpion is helping in the fight against cancer
DRUG: Chlorotoxin SOURCE: Deathstalker scorpion CONDITION: Cancer Radioactive scorpion venom might sound like the stuff comic-book villains would use. In fact it is 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 Africa and the Middle East. As the name suggests, its sting can be fatal. Within that sting lies a peptide called chlorotoxin, which has an unusual property – it sticks strongly to tumour cells while ignoring surrounding healthy tissue, by binding to a cancer-specific protein called matrix metalloproteinase-2. This tumourtargeting 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 tumour. This approach has been investigated by TransMolecular, a company based in Cambridge,
Massachusetts, as a way to treat glioma, a form of brain cancer. Chlorotoxin passed a phase II clinical trial in 2009. 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 tumour – 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 April 2011, TransMolecular’s tumour-targeter was snapped up by biopharmaceutical company Morphotek, a US-based subsidiary of Japanese drug giant Eisai. Though the company will not go into the details of its plans for chlorotoxin, spokesman Terry Cushmore says they intend to refine it before taking it into further clinical studies. “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,” he says. > 5 May 2012 | NewScientist | 35