You are likely aware of the large number of drugs that have been developed from chemicals found in plants, including aspirin from willow bark, atropine from deadly nightshade, and both morphine and codeine from the opium poppy. Indeed, more than a hundred-twenty, or over one-quarter of all drugs that currently exist, are derived from plants, although many of these have been chemically modified from their original form so as to improve potency and/or reduce unwanted side effects. However, increasing attention is now being paid to potential pharmaceuticals that are produced by other species, most notably the venomous animals that constitute about 15% of all species on the planet.
Venom is a toxin produced by an organism that is delivered to its target by biting, stinging or, in rare cases, by injection into the water (i.e., as for some sea animals). Animals that produce venom include not only snakes, spiders and scorpions, but also certain lizards, snails and even leeches, to name just a few. The biological purpose of their venom is to incapacitate or kill the target, for protective or ingestive purposes.
Venoms are typically composed of a complex mix of hundreds or even thousands of chemicals, which can include both peptides (short chains of amino acids) and neurotransmitters, molecules that nerve cells use to communicate with each other. Recent advances in chemical analytical approaches now allow even tiny amounts of venom to be analyzed in order to determine their constituent chemicals. However, importantly, in order to cause an effect in the target organism, that animal must have a receptor, a protein, to which these chemicals must bind. Hence, not all chemicals that are found in venom may have actions in humans, nor are all such actions deleterious.
One recent example of a ‘venomous drug’ is the discovery of a peptide in the salivary glands of the Gila monster lizard, Heloderma suspectum. Studies conducted by John Eng and his colleagues in the early 1990s at the Veterans Administration Center in the Bronx, NY, led to the isolation of several peptides that they named ‘exendins’ because they were both EXocrine (secreted into a duct) and ENDocrINe (secreted into the blood). While the venomous bite of the Gila monster is extremely toxic to humans, their studies identified a single constituent, exendin-4, as a ligand ( a molecule that can bind to a receptor) for the human glucagon-like peptide-1 (GLP-1) receptor. The rest of the story is now legend, as exendin-4 is a long-acting peptide that, like GLP-1 from our intestines, stimulates glucose-dependent insulin secretion and suppresses appetite. Indeed, a synthetic version of exendin-4, exenatide, was the first GLP-1-like molecule approved for the treatment of patients with type 2 diabetes (in 2005), beginning what we now often refer to as ‘the Ozempic era’ of diabetes control and weight loss.
But why exactly does the Gila monster produce a peptide in its venom that has such metabolic actions? The question was first addressed by Daniel Drucker at the University of Toronto in 1997 when he obtained several tissues from a Gila monster. Using molecular biology techniques, Dr. Drucker showed that this animal expresses a gene that produces exendin-4 in the salivary glands, in addition to the normal, intestinal gene for GLP-1. This study suggested that exendin-4 might play a distinct role from that of GLP-1 in the Gila lizard.
While the Exocrine role of exendin-4 in the venom of the Gila monster remains unclear, the cone snail is known to release insulin into the water as part of its venom. This leads to such severe hypoglycemia in its target, small fish, that they become confused and are more easily consumed. Hence, the insulin-stimulating/blood glucose-lowering effect of exendin-4 could, potentially, be part of its toxic actions on target organisms. Countering this hypothesis is a lack of evidence that humans bitten by a Gila lizard suffer from hypoglycemia, although it remains possible that insufficient levels of exendin-4 are injected during the biting process due to the size difference (i.e., the lizards only weigh ~ 0.5 kg). However, interestingly, a number of studies have demonstrated that blood levels of exendin-4 rise by up to 73-fold, in the lizard itself, as it chews its food, implying an ENDocrine role for exendin-4. Further studies are required to determine both the EXocrine and ENDocrine roles of exendin-4, although these are likely to be few and far between due to the current status of the Gila monster as a protected species.
In addition to exendin-4, a number of additional human ÎÛÎÛ²ÝÝ®ÊÓƵ have been isolated or modified from compounds in the venom of animals, many of which are consistent with the actions of the venom in the target prey. Hence, hypotensives have derived from the venom of snakes (captopril and enalapril). Similarly, several analgesics have resulted from studies on the venom of cone snails (ziconotide) and snakes (cobratide).
Interestingly, anyone who has gone swimming in the northern lakes of Quebec or Ontario knows the ‘ick’ feeling of stepping out of the water to discover a leech, or two or three attached to their skin. The author has similarly experienced this feeling in the lowlands of the Himalayan mountains, where the leeches are found not in the water, but in the trees and grasses where they drop down into your shirt neck or inch their way into your boots through the lace holes! However, whether aquatic or terrestrial, these leeches all have one factor in common – they attach onto your skin using a sucker, and then secrete a venomous peptide, hirudin, to prevent clotting as they feed on your blood.
Leeches have been used medicinally for millennia, from the dubious practise of blood-letting beginning in ancient Egypt through to their current use to promote circulation following limb-reattachment surgery (for example). However, it took the efforts of many scientists to develop the active component for modern therapeutic use. The anti-coagulant activity of leech venom was first reported in 1884 by Haycraft, followed by the identification and naming of the active component as hirudin by Jacoby in 1904. The isolation of pure hirudin did not occur until 1955 (Markward), followed by its sequencing (Dodt et al, 1984). This enabled rapid production of hirudin and the development of related, more potent variants using recombinant DNA approaches beginning in 1986 (Bergmann et al). Today, not only hirudin-based drugs, such as bivalirudin and desirudin, but also several similar compounds derived from snake venom (tirofiban, eptifibatide and batroxobin) are used clinically for the prevention of thromboses.
As unpleasant as the thought may be, the list of clinically-useful drugs derived from venomous animals is likely to expand as increasing numbers of scientists in universities and at pharmaceutical/biotech companies identify the chemical components of their venom and explore their biological actions.
Patricia Brubaker, Ph.D., F.R.S.C., F.C.A.H.S. is a Professor Emerita, Departments of Physiology and Medicine at the University of Toronto, Toronto, ON, Canada. Dr. Brubaker completed both her undergrad and PhD at ÎÛÎÛ²ÝÝ®ÊÓƵ University.
