The Medical Uses of Venom

There are over 100,000 animal venoms in the world. Animal venoms are complex mixtures of biological compounds, both enzymatic and non-enzymatic, that act mainly on ion channels or G-protein coupled membrane receptors, along with components of the clotting system. These are highly selective compounds with high affinity.

Early History

Venoms come from reptiles such as snakes, fishes, amphibians, insects and spiders, starfish and sea urchins, sea anemones, jellyfish and corals. Venoms are secreted in venom glands and delivered through spurs, stingers, fangs or spines. Their purpose includes killing and digesting prey, or self-defense.

Snake venoms have been used in traditional medicine for many thousands of years. Thousands of years ago, animal venoms were the basis of preparations meant to treat smallpox and leprosy and heal wounds. In the first century AD, theriac was developed, a mixture containing snake venom, that continued to be used until the 18^th century.

Albert Calmette discovered the method of antivenom preparation from animals injected with tiny doses of venom. First used only for this purpose, venoms have now been found to have multiple important uses. Cobra venom is among the most powerful analgesics known in minute doses, but is non-addictive, unlike morphine.

Venoms also serve as drug development libraries, each with over 100 different compounds – proteins, peptides and enzymes, as well as carbohydrates, lipids and other unidentified substances. Less than one in a thousand of these compounds have been characterized or even identified, out of the 10-50 million compounds that are available.

At present, many of these components are being examined for their potential as therapeutic applications. This is because cell surface receptors are major druggable targets, and because of the known bioactivity of many compounds in venom.

The main obstacles include sourcing high-quality venom samples, poor screening tests, practical difficulties in purifying and characterizing many of these molecules, and the small number of experts in this field.

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Drugs from Snake Venom

Snake venom has yielded a number of drugs used today, compared to other animal venoms. Firstly because it is relatively more abundant compared to the minute amounts produced by scorpions and snails. The first was captopril, based on the bradykinin-stimulating peptide. It was discovered by Sir John Vane from the Brazilian arrowhead viper (Bothrops jararaca). It is an inhibitor of the angiotensin-converting enzyme, which catalyzes the conversion of angiotensin I to angiotensin II. The current drug is a synthetic miniature form of the peptide modified for oral administration. Enalapril followed, substituting a potentially problematic mercapto group in captopril by an alkyl group. These are used to treat hypertension and cardiovascular disease, renal disease in diabetes patients and post-myocardial infarction heart failure.

Two other antiplatelet drugs have since been developed from snake venoms. They are Tirofiban and Eptifibatide, based on molecules called disintegrins that contain abundant cysteine, as well as the integrin-binding RGD/KGD motif. The first is a platelet glycoprotein GP IIb/IIIa integrin inhibitor from the saw-scaled viper Echis carinatus, while the latter has similar activity, but is isolated from Sistrurus miliarus barbourin, the Southeastern pygmy rattlesnake.

Another drug called Defibrase or Reptilase is commercially approved outside the USA, being a serine-like protease isolated from two Bothrops species. With thrombin-like activity, it converts fibrinogen into fibrin and is used extensively in China to treat stroke, pulmonary embolism, myocardial infarction and bleeding at the time of or following surgery.

Hemocoagulase is being used to inhibit platelet aggregation and thrombin activity, during plastic surgery, abdominal surgery and eye surgery. Ziconotide is a synthetic form of the ω-conotoxin M-VIIA peptide from the venom of Conus magus, a marine cone snail. It is used in many chronic pain conditions, acting by inhibiting neuronal N-type calcium channels.

Many other drugs are in the development stage. These include serine proteases like Viprin used in acute ischemic stroke to reduce clot formation. Another possibility being investigated is the use of serine proteinases to measure the levels of protein C and protein S in blood.

Another is from Bothrops jararaca, a platelet aggregating molecule. Vipera russelli venom yielded a Factor V inhibitor (RVV-V), and Russell’s viper venom-factor X activator (RVV-X). The latter is used to determine Factor X, and to screen for lupus anticoagulants. Ecarin comes from Ecaris carinatus and is a prothrombin activator, used to detect abnormal forms of the procoagulant protein prothrombin. The latter three are highly selective in their action.

Fibrin adhesives, which are good alternatives to sutures, have been developed using animal components and a serine proteinase from Crotalus durissus terrificus snake venom. Cobratide, from Naja atra, is used to suppress moderate to severe pain.

Some venom peptides may cross the blood-brain barrier (BBB), such as apamin from bee venom and chlorotoxin from scorpion venom. Their analogs can be used to label cancer cells in the central nervous system, for example, to make tumor excision easier.

Drugs from Non-Snake Venom

Lizard venom study yielded two approved synthetic analogs, exenatide and lixisenatide, which are used to regulate insulin secretion and suppress glucagon, thus helping to reduce body weight and regulate cardiovascular risk factors.

Leeches are the source of bivalirudin and desirudin, the first being synthetic and the second a recombinant molecule. Medicinal leeches are used to treat arthritis symptoms, microsurgery sites, infections and many other conditions.

Bee venom is also used in many different compounds to relieve pain in chronic conditions, such as osteoarthritis.

Bombesin from toads (Bombina bombina), Huachansu (from chansu, the dried venom from the toad  Bufo gargarizans), and Epibatidine from the Ecuadorian poison-dart frog Epipedobatus tricolor, are all being developed. They are being developed as anti-cancer drugs, and pain relievers more powerful than morphine.

Research Tools from Animal Venom

Several toxins are important research tools, the classic example being α-Bungarotoxin, isolated from Bungarus multicinctus. This is a very efficient and selective tool for the characterization of α7 and muscle-type nicotinic acetylcholine receptors. So are α-Conotoxins, which can identify different subtypes of these receptors and the different binding sites within receptor molecules.

Drug development from animal venom is a costly, risky and often unprofitable venture, and many biotechnology firms established to explore this field have since shut down.

Cosmetic Therapies

Drugs like anti-wrinkle cosmetics based on bee venom, and Argiotoxine-based compounds meant to suppress skin tanning, are also profitable.

Conclusion

More research is necessary to understand and exploit even the compounds undergoing clinical trials to ensure their safety, minimize off-target reactions and reduce adverse effects. Despite the exhausting and cumbersome process, animal venom studies are warranted to help discover effective and selective new drug and research molecules.              

References:

• Abd-el-Aziz, T. M. et al. (2019). Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving. Toxins. https://dx.doi.org/10.3390%2Ftoxins11100564. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832721/
• Utkin, Y. N. et al. (2015). Animal Venom Studies: Current Benefits and Future Developments. World Journal of Biological Chemistry. https://dx.doi.org/10.4331%2Fwjbc.v6.i2.28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436903/
• Bordon, K. de C. F. et al. (2020). From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2020.01132. https://www.frontiersin.org/articles/10.3389/fphar.2020.01132/full

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Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.