- A summary by Phill Robinson, Senior Aquarist at The Deep, Hull
Toxins are generally a mixture of different compounds, with each component being categorised into groups based on their basic biological action, for example; neurotoxins, affect the nervous system; hemotoxins, affect circulatory system and tissues; and cytotoxins, act on a cellular level. Advances in toxin research have led to the development of capabilities to identify and isolate specific components of a toxin and realise their pharmacological potential, enabling us to unlock an immense source of previously untapped novel drug leads.
One of the first venom derived drugs to be given FDA approval was Captopril, which is an Angiotensin-Converting Enzyme inhibitor and was developed in the late 1970’s, becoming available in the early 1980’s. The peptide in which the drug derives was first isolated from the venom of the Lancehead Viper, Bothrops jararaca. Captopril is derived a compound that acts through preventing the conversion of Angiotensin1 into Angiotensin2, which then results in an increase in the levels of Bradykinin (as Angiotensin2 breaks down Bradykinin).
Bradykinin is a natural part of the body’s immune system and one of its main roles is vasodilation. Because of this Captopril is prescribed and used as a medication for things such as; hypertension, to alleviate symptoms and increase the survival of people suffering cardiac conditions and to treat kidney issues that result from diabetes. The design and creation of Captopril was a key moment in drug discovery as, not only was this one of the first ACE inhibiting medications, but also because it paved the way for the future of novel toxin derived drug leads.
Batroxobin is a hemotoxic enzyme found in the venom of two Lancehead Viper species: Bothrops atrox and Bothrops moojeni (header picture) and is used to make two FDA approved medications, depending on which species the compound is from.
Defibrase® derives from the venom of B. moojeni and is generally used for the treatment of thrombotic ailments as it has anticoagulant properties through a combination of the targeted depletion of fibrin and the prevention of blood clotting.
Reptilase®, which comes from B. atrox, is used in the opposite way and serves as a means of reducing bleeding and promoting the coagulation of blood. It does this as the protein cleaves a specific peptide bond in fibrinogen, releasing monomers which are then involved in the formation of blood clots.
Tirofiban is a synthetic drug that has been modelled on Echistatin, a protein found in the venom of the Indian Saw Scaled Viper, Echis carinatus which acts to prevent aggregation of platelets and inhibit blood clotting. Tirofiban is a useful medication for people who are very likely to suffer heart attacks, as the prevention of blood clotting can occur as quickly as 10 minutes and it has a relatively short half-life, with clotting restoring to standard readings within a 4-8-hour window. This, coupled with the fact that the effects are reversible (should any detrimental effects occur), is why Tirofiban has proven itself to be beneficial in supporting other coronary drugs, such as Warfarin and Heparin in order to alleviate acute coronary syndromes.
Eptifibatide is based on peptide Barbourin, which is found within the venom of the Pygmy Rattlesnake, Sistrurus miliarius. Similar to Tirofiban, Eptifibatide is also synthetically developed and the disintegrins found within the venom of both species act as potent blockers of specific integrin receptors which are present on platelets. In normal situations the activated receptor would stimulate interactions between platelets and lead to the formation of a clot. However, with the addition of receptor blockers such as Tirofiban or Eptifibatide, the aggregation of platelets is inhibited and no clot is formed.
Exenatide originates from the exendin-4 peptide, a component of the venom from the Gila Monster, Heloderma suspectum, and is another which is synthetically produced. This peptide is extremely effective at generating a response within its target, which in this case is a peptide (GLP-1) which stimulates the production of insulin. Due to this it has become a drug lead to produce a treatment for type 2 diabetes. One of the significant factors that makes this an effective treatment is that when the GLP-1 receptor is activated by exendin-4, it remains active for a number of hours, in oppose to the several minutes of activity that GLP-1 naturally triggers.
Alongside being recognized as a treatment for type 2 diabetes, the activation of GLP-1 receptors have shown to display neuroprotective effects and results from early pre-clinical studies have found that receptor stimulation by exendin-4 may provide an effective treatment for two well-known and debilitating diseases: Alzheimer’s and Parkinson’s.
There are also early trials which have shown exendin-4 has anti-tumor activity in human prostate and pancreatic cancer cells as well as displaying control over the increase and metastasis of ovarian cancer cells in mouse models.
Finally there is Prialt®, which is made from the synthetic peptide Ziconotide, a peptide modelled on peptides from the venom of the Cone Snail genus Conus. These are neurotoxins that act as blockers of voltage-gated calcium channels, which play an important role in the release of an array of neurotransmitters. The potent inhibitory effect on the calcium channels leads to strong relief against both nociceptive and neuropathic pain. The significant antinociceptive properties of Ziconotide are not the only medically important aspect of this drug as it also removes the risk of some of the more severe negative side effects which can be encountered with opioid-based analgesics.
