What's your poison?

21 November 2016

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To most of us, drugs come from the pharmacy: home of bottled remedies and packaged pills. However, the origins of medicine can be much more exotic than your local chemist. The first HIV drug, for instance, was derived from a sea sponge, while a drug to combat heart disease arose from the foxglove plant, but some medicines come from a much more dangerous place.

Deadly venomous creatures, which inject poisonous substances into their prey with bites or stingers, might hold the key to treating many tricky conditions. Following hundreds of millions of years of evolution, the toxins in venoms have been honed to target specific components of their prey's bodily function. Deadly venom contains a cocktail soup of toxic proteins and peptides, which are short strings of amino acids similar to proteins that can be used as therapeutics.

As all venom is multitasking, these molecules might have different targets and effects. Some of them go for the nervous system and break down the nerve-to-muscle communication, causing paralysis. Yet, it's these same toxic properties that could make great drugs. A few of them are already in trials to cure brain tumours, heart failure, diabetes, erectile dysfunction and autoimmune disorders, specifically targeting anything from the heart to the brain.

Dancing with death

Venom is nature's most efficient killer. In the evolutionary battle between predator and prey, weapons and defences are constantly tweaked. However, venom-based therapies aren't anything new. They showed up in Sanskrit texts from the second century A.D. and later, shamans were applying steppe viper venom to Romans wounds. Cobra venom was administrated for centuries in traditional Chinese and Indian medicine, even before it was introduced to the West in the 19th century as a homeopathic pain remedy. However, the curative dose was just within the limit of the fatal dose and, walking such a fine line, doctors hastened patients' deaths about as often as they reduced their pain.

venom snake

The science of converting deadly venoms into medicines took off in the 20th century, when Hugh Alistair Reid suggested that the snake's venom might be used against deep-vein thrombosis, as one of its proteins prevents clotting. After the same clot-busting drug, Arvin, had reached hospitals in Europe, it was then replaced by other venom anticoagulants.

As one can't just put harmful venom in a tablet and hand it to patients, the researchers have to tease out the valuable bits of the venom and alter them at the molecular level - resize and tinker them in order to survive the harsh effects of the human gut. For example, researchers have now developed a new class of drugs for heart disease by identifying a component found within pit viper venom that plays a key role in lowering blood pressure.

In this era, heart disease sufferers owe gratitude to a deadly African tree snake - known as the Eastern green mamba, whose venom impairs its victim's blood circulation. The beauty of the venom is that its key peptide component lowers the blood pressure and shields the kidneys from an overload of salt and water. As well as tackling heart disease, snake venom also displays great potential to act as a powerful painkiller. Another snake, known as the black mamba, whose open mouth mirrors a coffin (and whose venom can swiftly put you in one) hold toxins that can relieve chronic pain, a condition that is difficult for clinicians to treat effectively.

Venomous pain relief

Mambalgins, a group of protein found in snakes, were discovered when hunting for alternatives to opiate drugs such as morphine. Opiates often cause side effects such as nausea, constipation and drug dependency, with people often needing higher and higher doses to feel the same effects. In 2014, drug overdose was the leading cause of accidental deaths, so an alternative option for pain relief would be incredibly valuable to society.

Pain can be very useful from an evolutionary point of view as it is nature's way of telling the brain about injury to the body. The pain signal is closely linked to what is known as the "Flight or Fight Response". This is where our body is put on high alert. Our muscles contract, receiving more oxygen, our heart beats faster, our breathing speeds up and we get ready to stand and fight or run from the danger.

Cone Snail

While pain can be useful, for many people it can seriously debilitate, or indeed ruin, their life. When you're hurting, pain signals travel up to the brain, however there are other signals which can travel down from the brain which can form a blockade, restricting the pain signals. These blocks can be opened or closed, allowing the pain signals through or causing pain to be blocked, respectively.

Nerve cells called nociceptors synthesise a wide variety of these blockades, in the form of proteins that make pores in the cell membrane. These pores open in response to different types of stimuli, allowing electrical current, in the form of sodium, potassium, and other ions, to flow in or out of the cell. This triggers nervous impulses that spread to the spinal cord which are then sent to the brain.

With almost 15% of the world population suffering from chronic pain, the venoms which act on these proteins are nothing short of medical superstars. So far, there is one venom-based painkiller that has hit the market: Prialt (ziconotide), which mimics the venom of the cone snail. Prialt's peptide acts on the nervous system and inhibits the ability of neurons to transmit pain signals to the brain.

Taking the sting out of spider venom

As well as the venom from snakes and cone snails, scientists are also checking every nook and cranny of the animal kingdom, and another creature which is proving promising is the spider.

Sidewinder Snake

Spider milking involves a scientist gingerly picking up a spider and giving it an electric shock, while another researcher rushes to draw the venom from the fangs into a syringe. Usually, hundreds if not thousands of hairy crawlers are needed to get a useful amount of this venom; scientists need to milk one tiny spider hundreds of times just to obtain a single milligram.

Spiders have a bad reputation, but, for pain researchers, they are a dream come true. These eight-legged creatures bare two venom glands, containgin chemicals designed to kill their diet: insects. Delivered through stiletto-sharp fangs, spider venom shuts down a victim's central nervous system and targets several biological receptors, rendering it paralysed - or dead - so the spider can turn its prey into mush and gulp down the organ soup.

Brazilian Wandering spider

Since the signal-accepting proteins, or receptors, of insects are not poles apart from mammalian ones, a large proportion of the molecules found in spider venom could also target human receptors, for example ion channels, which are proteins that allow ions to cross the cell membrane and communicate across the cell. These molecular antennae open and close to expose the guts of a cell to both the outside world and also receptors that pick up chemical signals from the surrounding environment. However, the venom hacks the network and shuts down this communication.

Peptides that make up a substantial part of spider venom block the sodium ion channels, which all nerve cells use to generate nervous impulses, and modulate ionic currents across these channels. Critically, the therapeutic potential of peptides from the spider venoms is largely due to their selectivity and affinity for ion channels and other receptor, which could have implications in treating chronic pain and muscular diseases.

The sting in the tail: what's next?

All these promising molecules are likely to be just the tip of the iceberg. For example, it is predicted that less than 0.01% of roughly 10 million active compounds found in spider venoms have risen to fame. The prospective catalogue of peptides is remarkable and, with the ever present threat of devastating diseases and conditions, these venomous players could yet have the unrealised potential as important medicines. As for the future, expect to see more and more drugs inspired by nature's powerful venoms coming to a pharmacy shelf near you.

 

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