In the search for better, faster, stronger drugs, animal venom could be the answer, as toxins are harnessed to create target-specific treatments.
The medicine of the future may have venomous origins. The swift efficiency of animal venoms that can still hearts, paralyse nerves and suffocate prey and predator alike relies on targeting specific biological systems. But within the chemical cocktail of venom, one species’ downfall could be another species’ saviour. In the pharmaceutical industry, some are shifting their focus away from synthetically derived molecules back to biologics — compounds that initially come from biological sources. Researchers have returned to being biological prospectors, mining nature for new chemical compounds that just might yield new medicinal drugs.
Venom became a serious contender in modern drug discovery in the 1970s, with the development of the blood pressure drug Captopril based on the venom of the Brazilian viper (Bothrops jararaca). Since then, there have been six FDA approved drugs derived from venom, with many more in the queue for clinical trials.
Biologics already have a firm and multi-pronged foothold in medicine. This is because biologics are simply any products used to prevent or treat disease that have been isolated from or based upon natural sources. In the early days of medicine, most drugs were made from plants which were known to have some sort of medicinal use. Yet whether these compounds are sourced from tree bark, animals or microorganisms (like vaccines), they all fall under the banner of biologics.
But where chemically synthesised drugs have their individual chemical structures tailored in the laboratory and custom designed for a purpose, biologics are confusing mixtures. Even after sorting out this tangle of chemicals — including many that have yet to be identified — it is hard to find out exactly which molecule in the mixture is responsible for the toxic response.
So why venom?
Venom wielders span across almost every taxa of the animal kingdom. From one appendage to many, the diverse suite of animals includes reptiles, spiders, centipedes, cone snails, box jellyfish, sea anemones and platypuses. But don’t mistake venom for poison. Venom is a toxin which must be injected into their foes via a bite or sting — whereas poison is absorbed, consumed or inhaled by the hapless victim.
What makes venom so attractive in the current drug discovery field is that it has already gone through the most rigorous testing phase, that synthetics can never replicate: evolution. A chemical cocktail millions of years in the making, evolution has streamlined the venom found in different species, exploring multiple trajectories to create the highly efficient toxins we see today. The origin of the venom system in some species can be traced back to ancient hormones and proteins – by-products created from the need to immobilise, defend or attack.
Venom was formulated with the purpose of disruption and disorder, a complex concoction of proteins, enzymes, peptides, inorganic salts and molecules. Each class of venom has a certain preference and affinity to a certain biological target. Once injected into a target animal, it swiftly locates and attacks this molecular component with unerring accuracy. That disruption wrecks havoc with biological systems in our body that we usually take for granted. Depending on the target, there is a wide spectrum of consequences. Venom can stop blood from clotting in the circulatory system, cause paralysis of nerves and even kick-start necrosis (premature death of cells) in tissues and muscles.
What makes venom such an attractive subject for pharmaceutical development is its molecular architecture. As Professor Glenn King from the Institute for Molecular Bioscience at the University of Queensland explains: “The compound is very small, and also very disulfide-rich, which makes it very stable in biological fluids such as serum and able to persist in the human body.” These disulfide bonds act as anchors to lock in the various twists and folds of the molecule. Without any sprawling chemical arms, the compound is extremely hardy, making it immovable against chemical or heat stress and resistant to attack by enzymes.
“The way we look at it, venoms give us a pre-optimised library of disulfide-rich peptides,” said Prof King. “So you have these molecules that have evolved over many millions of years, these small stable peptides that we are very interested in from a drug discovery point of view.”
In the field of drug discovery, the specificity, stability and efficiency already tweaked to perfection by nature make venoms great potential sources for new medicinal drugs. Prof King emphasised that the finely honed specificity of venoms is especially evident in insects, as their toxins are only specific to insect prey species: “There are over 100,000 species of spiders in the world at present, and there are only a handful that are potentially lethal to humans, namely the funnel web spider, the redback spider, the recluse spider and the Brazilian armed spider. Most spiders are intrinsically harmless to humans."
But forget flashy venomous creatures like snakes, Professor King has turned to creepy crawly pals for our next medicinal fix. His research team have teased out compounds from the funnel web spider, tarantulas and more recently, centipedes.
“There are over 3000 species of centipedes and they are all venomous. They are not dangerous to humans, but they can give you a very painful bite. There has not been a single fatal case from a centipede bite,” said Professor King.
But before unspooling the chemical potential of venoms can even begin, you need to milk it straight from the source. And when it comes harvesting venom from a total 3000 Chinese red headed centipedes (Scolopendra subspinipes mutilans), this is no small feat. A small electrical current is applied to the forcipules — a set of pincer like claws — which causes venom to be secreted through a small pore. The forcipules are the evolved legacy of what used to be a pair of walking legs, but now they have a renewed purpose as a venom delivery system completely unique to centipedes. The harvesting process is repeated over a number of hours, as centipedes can only release a few precious microlitres of venom at a time.
Although centipedes were the first species on land to use venom over 400 million years ago, they represent uncharted territory within venom research. “They are highly successful predators, but their venom has not been studied in detail. So we decided it was time to look at their venom, which targets the nervous system,” said Prof King.
In the case of the Chinese red headed centipede, the efficacy of its venom had already been tested during the evolutionary process to create a highly successful neural interrupter which paralysed insect prey. Among all the active compounds in the venom, each component had to be separated and then isolated individually before the exhaustive list could be narrowed down to find which disulfide-rich peptide was responsible for the action of the venom. Sifting through the molecular mix in the centipede venom, Prof King’s research team was able to isolate and purify one peptide with potential.
The compound that was extracted was found to be a potential painkiller and might be used to help those suffering from chronic pain. Called Ssm6a, the purified peptide can effectively block a protein responsible for pain transmission without the side effects that usually accompany addictive opiate drugs such as morphine.
But what stood out about Ssm6a was the target. Here, the elegance of using a toxin originally geared towards an insect target becomes apparent. While humans have nine voltage-gated sodium channel proteins involved in the chain of electrical signalling in neurons, insects only have one. When venom from the Chinese red headed centipede is used on insect prey, Ssm6a blocks this single channel. But in humans, Ssm6a selectively targets just one of these nine channel proteins, called Nav1.7.
This specificity means that the venom had 150 times more affinity for Nav1.7 than other Nav proteins. On the other hand, current painkillers act broadly across multiple Nav channels, encroaching on the territory of heart and muscle function. This overlap across channels means that taking painkillers like morphine comes with the risk of heart and muscle failure. Since Ssm6a targets Nav1.7 specifically without this overlap, these side effects are likely to be reduced. Mice models injected with a high dose of Ssm6a showed greater tolerance to pain tests, providing encouragement that this could be brought to market as a new painkiller.
The drug discovery research conducted by Prof King’s team is a demonstration of how the desirable traits found in the chemical cocktail of venom can be harnessed in the development of new drugs. Alongside the centipede, Prof King mentioned that they were also focussing on other arthropods that have been neglected in venom research: “We are now looking into a group of even more successful species called assassin bugs.” There is vast untapped potential here as there are over 7000 species. “The venoms of these animals have never been studied in detail,” he added.
As researchers continue to meticulously search among the chemical cocktails of venom, they may find molecules that hold the key to new pharmaceuticals. The allure of venom-based drugs is their ability to target specific biological processes, which triumphs over synthetically created drugs. In the search of newer, more effective medicines, the nature of drug discovery may just get a little more toxic.
Edited by Tessa Evans and Bryonie Scott, and supported by Olivier Restif.