“THERE are no poisons, only poisonous doses.” Thus did Paracelsus, the greatest of the alchemists, encapsulate an important piece of medical wisdom. In fact, that is only half the story, for many materials which are toxic at high doses, when used sparingly and directed at specific targets, are not merely harmless, but actually beneficial. Plant poisons, from digitalis to curare, are routinely employed as drugs. And now it is the turn of animal toxins, as researchers examine venoms secreted by snakes and lizards, to see if they, too, might be turned into treatments.
Snake venom, collected from farmed reptiles, has been used to make antisera for snake bites for decades by injecting it into mammals such as sheep and horses, and collecting the antibodies thus generated. Making drugs from the venom itself, however, is a fairly new idea. But that is what Stefan Hailey of the University of Delaware and his colleagues hope to do. In a paper published recently by Toxicon, they report how a protein called eristostatin, which can be extracted from the venom of the Asian sand viper, helps people’s immune systems fight malignant melanoma. Previous studies have shown that eristostatin stops melanoma cells colonising the liver and lungs in mice. Dr Hailey is trying to work out how this happens.
Eristostatin’s day job is to stop victims’ blood clotting and thus plugging up damaged blood vessels after a bite. By increasing blood loss, it weakens victims. The molecule does this by glomming onto cellular fragments called platelets that are crucial to the process of clotting, thus disabling them. Dr Hailey hopes to make use of this tendency to encourage the immune system to attack melanoma cells. His idea requires eristostatin to be as attracted to cancer cells as it is to platelets.
Two observations suggest it could be. One is that eristostatin has a particular affinity for melanoma cells, which presumably have a protein on their surfaces that is similar to the one which attracts eristostatin to platelets. The other observation is that when eristostatin is attached to a cell’s surface it attracts the attention of T-lymphocytes. These are immune-system cells whose job is to kill other body cells that have been infected with viruses, or which have turned cancerous. If melanoma cells could, in this way, be made especially attractive to T-lymphocytes, that might clear away the tumour completely.
Dr Hailey and his colleagues used a technique called atomic-force microscopy to study the interactions between melanoma cancer cells and eristostatin. This technique allows the force required to pull the two apart to be measured precisely, to see whether there is a genuine attraction—which he found that there is.
If eristostatin does prove an effective means to treat cancer, it will join a growing stable of medicines derived from reptile toxins. Tirofiban, for instance, is a modified version of another anticoagulant—in this case from the venom of the African saw-scaled viper. It is given to people with angina, and also to those who have had heart attacks. Exenatide is the synthetic form of a hormone called exendin-4 that occurs naturally in the saliva of the Gila monster, a venomous North American lizard. It works as a treatment for type-2 diabetes because it increases insulin production in those whose blood-sugar levels are high. And captopril, a blood-vessel-relaxing agent widely used to treat hypertension, is based on teprotide, from Brazilian arrowhead vipers, which helps the other toxins in the venom circulate quickly, and thus reach their targets rapidly.
The year of the snake
There are other venom-based drugs in the pipeline, too. Crotoxin, a protein from the South American rattlesnake, though not yet approved for use, may one day be employed to treat cancers. Crotoxin seems particularly attracted to cancer cells. One portion of the molecule recognises a protein on the cell’s membrane, and links to it. The other portion damages the membrane, triggering a mechanism called apoptosis which causes the cell to kill itself. Celtic Biotech, based in Dublin, is running a series of tests using this molecule on cancer patients at the Georges Pompidou European Hospital in Paris. This year, Celtic plans to try it on people with several different sorts of cancer, since the firm’s researchers believe it should be effective on all solid tumours. If those trials are successful, though, they then plan to concentrate on lung cancer, the largest market.
Perhaps the most astonishing toxin-derived drug of all, however, is hannalgesin, which is made from king-cobra venom. Kini Manjunatha of the National University of Singapore is developing this substance as a pain-relieving agent. He claims it is between 20 and 200 times more effective than morphine. Moreover, unlike morphine, which is usually injected, hannalgesin can be taken by mouth. He is planning to run the first clinical trials at the end of 2013 or in early 2014.
Venom, then, is proving to be a trove of useful molecules. At a time when drug companies are struggling to develop new products, a novel source of raw materials that have been road-tested by natural selection, and merely need to be subverted from their original purposes rather than created afresh, must be welcome. It is not turning base metals into gold, as Paracelsus and his kind once attempted. But as a transformation of matter, it is surely a far more valuable trick.
Jan 5 2013
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Drug Research || Toxic Medicine