At first glance, it may seem surprising to learn that the venom of a tarantula could be an alternative to powerful painkillers such as morphine. But although this is not a well-known —or even widely exploited— avenue of research, science has been studying animal venom as a potential source of new drugs for decades. The first such drug approved for use in humans, in 1981, was captopril, a compound for the treatment of hypertension, developed from a molecule identified in the venom of the pit viper Bothrops jararaca.
If nature is to continue to amaze us with these new ideas for combating pain and disease, it is essential to protect biodiversity. The sustainability of the planet and that of the pharmaceutical industry —ready to take advantage of this new source of inspiration and innovation— converge with the curiosity of researchers to learn more about these feared (and often delicate) species.
From the snake to the pharmacy
To date, only 11 compounds derived from animal venom have been approved for use as medicines in humans. One of them is batroxobin (also known as reptilase), a protease enzyme present in the venom of the snake Bothrops moojeni and other species of the genus Bothrops. This toxin is the basis of treatments for thrombosis and myocardial infarction, and its use as a medicine was approved in Japan in 1989.
The venom of these snakes produces lethal haemorrhages in their prey, usually rodents and other small mammals and birds, as well as frogs, lizards or tarantulas. Through the purification and isolation of the venom extracted from live snakes, batroxobin began to be obtained as an active ingredient for medical use. This is unusual in the pharmaceutical industry, where drugs are usually synthetic analogues (because the animal source is limited). And this process usually concludes with the use of molecules derived from the original compound, in which some modifications have been introduced to optimise their effectiveness or selectivity, to eliminate their possible toxicity and to facilitate their administration and entry into the human body. In the case of batroxobin, an important advance in its production was to turn to biological synthesis: by means of genetic engineering, microorganisms such as yeasts are able to manufacture the enzyme.
Spiders, bacteria and cosmetic treatments
Apart from their medicinal uses, pharmacologically active compounds identified in animal venoms have other important clinical applications: as models for synthesising new molecules, as diagnostic tools, and also as cosmetic treatments. In fact, cosmetics is currently the sector that obtains the most revenue from animal toxins. The most obvious example is botulinum toxin or Botox, isolated from the bacterium Clostridium botulinum and whose sales exceed 3 billion dollars a year.
Another less well-known example of cosmetic application is Argiotoxin-636, isolated from the venom of the spider Argiope lobata and which inhibits melanin formation. It is thus applied in skin whitening and depigmentation treatments.
Gila monster, enormous promise
Exenatide is a synthetic drug derived from a compound identified in the venom of the Gila monster (Heloderma suspectum), a hefty, slow-moving lizard up to 60 centimetres long that is believed to use venom to defend itself, rather than to hunt. Exenatide was approved in 2005 by the FDA (the US Food and Drug Administration) and in 2009 by the EMA (the European Medicines Agency) for the treatment of type 2 diabetes. The same compound is currently being studied for possible application in the treatment of Parkinson’s patients.
Until relatively recently, most of the animal toxins studied came from snake or lizard venoms. The main reason —besides the fact that these venoms are the most well-known because of their high lethality— is that, due to their size, these animals produce a greater amount of venom per specimen than other animals such as insects, arthropods or spiders. However, the relatively recent development of increasingly sensitive analytical techniques and instruments has allowed researchers in this field to turn their gaze towards smaller and smaller creatures, thus greatly expanding the catalogue of potential candidates.
A new pharmacy at the bottom of the sea
The predominance of reptiles as a source of medicine is also due to the fact that they are terrestrial animals, much more accessible than marine organisms. The pharmacological study of animal venoms is a very young discipline, and we could say that it is still taking its first steps in the case of toxins from the countless venomous creatures that inhabit the oceans. Ziconotide is the only marine organism-derived drug approved by the drug agencies for use in humans, receiving the green light from the FDA in 2004 as a treatment for chronic pain.
Specifically, Ziconotide is a synthetic analogue of a molecule isolated from the venom of the sea snail Conus magus, which inhibits nerve impulses and the release of neurotransmitters in the thalamus, where the brain’s pain centre is located. Ziconotide is considered a much more powerful analgesic than morphine, its main advantage being that, unlike morphine and other opiate substances, it does not generate dependence or tolerance.
The neurotoxic potency of the venom of these conical-shelled sea snails was already known by naturalists. Most of these species do not represent a great risk to humans —they are small and feed mainly on worms— but the larger ones are dangerous, as they feed on fish —which they instantly paralyse with their venom— and can even kill humans. One of them, Conus geographus, is popularly known as the cigarette snail, due to the saying that after being stung by this creature, “the victim will only have enough time to smoke a cigarette before dying.” Gallows humour and exaggeration aside, it is important to warn of the lethal risk involved in harvesting its tremendously attractive shells, which are within easy reach on beaches and tropical reefs.
Tarantulas as a new icon of biodiversity
In April 2020, Australian researchers announced that they had designed an analgesic drug, based on a molecule isolated from the venom of the tarantula Cyriopagopus schmidti. Although it has yet to pass clinical trials, it is seen as a very promising alternative to opioid treatments for chronic pain, as it does not cause either dependency or the usual side effects associated with them, such as nausea.
It is one of the latest examples of potential medicines found in animal venoms. This is a field of research that has barely begun to bear fruit and whose greatest value is not that it finds new compounds with pharmacological properties, but that in many cases the properties themselves are novel. In other words, they have different operating mechanisms from those of typical medicines. Venoms are mixtures rich in proteins, peptides and neurotransmitters that attack prey or enemies by interfering with metabolic pathways in the body or biochemical reactions in the cells. In the case of this tarantula, researchers have discovered in its venom “a mini-protein, known as Huwentoxin-IV, that binds to pain receptors in the body.”
And these examples are one more powerful reason to be concerned about and protect the environment and ensure the sustainability of the fragile ecosystems that share the planet with us. Who knows if in them, and in some of their venomous inhabitants, we will find the remedy for currently irreversible ailments, or perhaps even for future pandemics.