Gur Roshwalb, M.D.

The Poisons and Venoms of Organisms Are a Treasure Trove for Potential Human Drugs

Nature has been providing medicines to treat our diseases and relieve our suffering for many thousands of years. As noted by Harvard University’s Center for Health and the Global Environment, despite great advances in rational drug design, most prescribed medicines used in industrialized countries today are still derived from—or patterned after—natural compounds from plants and animals. And this is likely to continue into the foreseeable future.

Plants to the Rescue

Consider first how plants have enriched our ability to treat patients. Aspirin is now manufactured synthetically, but the active ingredient—salicylic acid—was originally an extract from the bark of the willow tree. The ancient Greek physician Hippocrates wrote about its use to relieve headaches and fevers; and today it is also widely used to prevent heart attacks and stroke due to its effectiveness as an anticlotting agent.

What about high cholesterol? A substance called guggulsterone, which comes from the sap of the guggul tree of India, has been shown to block a protein called the farnesoid X receptor, or FXR, which plays a role in cholesterol metabolism, converting cholesterol in the blood to bile acids. Elevated bile acid levels can boost cholesterol; thus, blocking FXR may bring cholesterol counts down.

And this is just barely scratching the surface. Taxol (paclitaxel)—which saves the lives of countless women with lung, breast, uterine, and other cancers—comes from the bark of the Pacific yew tree. Meanwhile, because of drugs developed from the Madagascar rosy periwinkle, including the derived compound vincristine, children no longer inevitably die of leukemia or lymphoma. 

Many Drugs from Microorganisms

Consider that microbes—microscopic fungi and bacteria—have given us nearly all of our antibiotics such as penicillin; the cholesterol-lowering statins; and rapamycin (also known as sirolimus), which is used to coat arterial stents so that the cells lining the arteries opened by the stents do not divide and reclog them.

Clues from the Animal Kingdom

Turning away from plants and microorganisms and taking a look at the animal kingdom, we find that nature’s bounty has been just as generous to us. Even the humble tunicates—better known as sea squirts—have played an important role in the discovery of several promising drugs. For example, researchers found a cancer cell-killing molecule called ecteinascidin 743 (ET-743) in a type of sea squirt living in the reefs and swamps of the West Indies. That molecule was subsequently utilized outside the U.S. for soft-tissue sarcomas and has entered U.S. clinical trials for several cancers.

The first effective remedy against AIDS in the 1990s—azidothymidine (AZT)—was modeled on a compound isolated from an obscure sponge, Cryptotethya crypta (also known as Tectitethya crypta), originally discovered in the Caribbean in 1949. Other sea creatures, called bryozoans, produce a substance call bryostatin that some believe looks like a potential treatment for Alzheimer’s disease.

Venomous Victories

In one of the odd twists of fate that make the topic of medicines derived from animals so fascinating, one of the most fruitful places to look within the animal kingdom is the vast array of poisons and venoms that organisms have evolved to ward off predators or to attack prey. More than 30 years ago, Capoten (captopril)—copied from a pit viper venom peptide—became the first approved venom-derived drug (in this case for hypertension). Several venom-derived drugs have since been approved for cardiovascular disease, as has a venom-derived painkiller. Today, thanks to increasing knowledge of the human nervous and immune systems, the pipeline “from fang to pharmacy” (as The Scientist memorably described it in 2013) is growing ever bigger.

Scorpions are proving useful in medicine as well. As reported recently by Christie Wilcox in her book Venomous: How Earth’s Deadliest Creatures Mastered Biochemistry, researchers are at work on a “tumor paint” known as BLZ-100, derived from scorpion venom, which causes rapid paralysis in insects. This targeted contrast agent, which is being used in clinical studies for children’s brain tumors, binds to chloride channels found in tumor cells; thus, by linking this toxin to a fluorescent dye, doctors can see and remove an entire cancerous mass.

Another venom-derived drug comes from the sun anemone Stichodactyla helianthus, which lives on reefs in the Caribbean and uses its soft green tentacles to stun shrimp with a cocktail of toxins. Physiologists have shown that one of these toxins, a peptide called ShK, is a potent inhibitor of a T-lymphocyte potassium channel called Kv1.3, the upregulation of which is implicated in autoimmune diseases. And a poison produced by the cone snail Conus geographus has been shown to be 1,000 times more powerful than morphine in treating certain kinds of chronic pain. For example, the snail-derived drug Prialt® (ziconotide) jams up nerve transmission in the spinal cord and blocks certain pain signals from reaching the brain.

The tropical forests and savannahs of Argentina, Brazil, and Paraguay are the habitats of the feared pit viper Bothrops jararaca (also known as the fer-de-lance). Snakebites from this species often result in the victim’s collapse due to a massive drop in blood pressure. A research effort has worked out how the viper venom causes that blood pressure decrease and exactly what chemical in the venom is responsible. That knowledge led to abatement of morbidity and mortality from the pathological effects of chronic high blood pressure, via the creation of so-called angiotensin-converting enzyme (ACE) inhibitors. As another example, the diabetes drug exenatide, which lowers blood sugar and increases the body’s production of insulin, is a synthetic version of a component exendin-4 in the saliva of Gila monsters, large venomous lizards found in the southwestern U.S. and northwestern Mexico.

Finally, one of the more unlikely inspirations in recent years involves one of the natural world’s least-celebrated liquids: the saliva of the tick Ornithodoros moubata. A new inhibitor of the complement protein C5, a small recombinant compact protein named Coversin, has been derived from a protein in the tick’s saliva. The natural Coversin molecule works by damping down the immune response of the host animal that the tick feeds off of, enabling it to feed repeatedly without damage from host inflammatory substances. Coversin is currently being studied as a potential treatment for rare autoimmune diseases, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and Guillain-Barre´ syndrome.

Despite the challenges involved—on average, only one in thousands of natural compounds tested shows pharmaceutical promise and only a handful of those ever make it to market, according to Scientific American—researchers press on. Mother Nature, with millions of years of experience under her belt, continues to be the ultimate drug developer.

Gur Roshwalb, M.D. ([email protected]), is CEO of Akari Therapeutics. 

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