Deadly animal venom could lead to pharmaceutical breakthroughs

You don’t want to get bitten by a Brazilian viper.

Their venom fuels a victim’s blood pressure, which helps them stun their prey in the wild, of course. But when they bite humans, it can cause swelling, pain, kidney failure and even brain hemorrhages. There’s a reason the serpent gender Bothrops kills more people in the Americas than any other gender.

In the 20th century, Sir John Vane, who would later win the Nobel prizeand his colleague Sérgio Henrique Ferreira had a radical idea: what if they modified one of the active components of the venom of the Brazilian viper to lower blood pressure in hypertensive patients?

From venom to medicine

The snake’s venom inhibits a molecule called angiotensin converting enzyme (AS). Normally, this enzyme plays a vital role in regulating blood pressure. When ACE is inhibited by a snakebite, the victim’s blood pressure drops through the ground.

In collaboration with a pharmaceutical company, the duo developed a synthetic mime of one of the active components of venom. This drug, called captopril, became the first ACE inhibitor approved by the FDA. Experts say the discovery revolutionized how doctors treat cardiovascular disease.

Today, snakes are just one of many poisonous animals that scientists look to for inspiration in drug discovery. For instance, exenatide is a type 2 diabetes treatment based on Gila monster venom, ziconotide is a conical snail venom-based analgesic and desirudin is a blood thinner used to treat blood clots in a deep vein made from leech toxins.

It may seem counter-intuitive to search for deadly venoms in search of life-saving drugs, but the two have more in common than you might think. As venomous predators and their prey engaged in an evolutionary arms race, natural selection has caused venoms to become extremely precise, fast-acting, and potent in the body – all desirable qualities for effective medicine.

The biochemistry and evolution of venom

Scientists estimate that there are more 220,000 poisonous species, ranging from jellyfish to mammals. This represents 15% of the animal diversity of the Earth.

This astonishing biodiversity is also accompanied by chemical diversity. Venom is not a single molecule. It’s a complex cocktail of peptides and enzymes that disrupt another organism’s physiology, says Helena Safavi, a biochemist at the University of Utah and the University of Copenhagen. Some of the more complex spider and cone snail venoms can have thousands of components.

You would probably never use a whole venomous mixture in medicine, Safavi says. “But because it’s such a complex mix of things, we can go and look at the individual components which, when given as an individual entity, can be therapeutic.”

Sometimes the effect of the poisonous peptide in humans parallels its effect in predator-prey interactions. For example, the conical snail Conus geographusa deadly fish hunter, releases insulin in its venom. This causes the fish’s blood sugar to drop, stunning it so the snail can capture and eat the fish. The snail’s insulin works at lightning speed – it Needs be quick so the fish don’t escape.

Insulin can activate quickly because of the way it is packaged. Human insulin comes in a six-molecule pack that takes up to an hour to break down and use. Meanwhile, the snail’s version exists as a single molecule ready to react when called upon. The Safavi team took inspiration from snail insulin to edit human insulin be fast acting and potent for diabetes management.

Read more: Cone Snail Venom is a source of untapped potential for the treatment of chronic pain

Other venom-based drugs might have less intuitive pharmaceutical applications. For example, the FDA-approved pain treatment PRIAL, also called ziconotide, is also made from conical snail venom. It may not be pain relief from fish predation, but it can reduce chronic pain when injected into the spine of HIV and cancer patients.

“In order to capture their prey, [cone snails] knock out their sensory systems,” says Baldomero Olivera, a biochemist and neuroscientist at the University of Utah. “Things that inhibit sensory neurons are usually candidates for potentially inhibiting circuits that send us pain.”

Perhaps one of the most original ways to use venom in medicine is to treat cancer. Mandë Holford, a marine chemical biologist based at the City University of New York Hunter College and Graduate Center and the American Museum of Natural History, is leading the way in venom-based cancer treatments.

The logic is as follows: cancer cells overexpress certain cellular channels. Holford’s team identified a compound in the venom of augers, a close relative of cone snails, that block one of these channels. When injected into tumor-bearing mice, it inhibits liver cancer proliferation and tumor size. For the most part, the treatment spares non-cancerous cells, so it might even alleviate the list of side effects of traditional chemotherapy, according to Holford.

“It seems like a really smart way to try to deal with this very intractable problem that we have,” says Holford.

The road from venom to treatment

The process from venom characterization to FDA approval is long and arduous.

“[Companies] want the research to be quite advanced before they start spending a lot of money on it. We academic labs don’t have those resources, and we usually don’t have the expertise,” Safavi says.

Yet some researchers say the biggest hurdle comes before translation. “The problem in most cases is that we don’t understand the molecular correlates of many diseases,” says Olivera.

Holford adds that there is a similar gap in the basic understanding of venom. “You can’t reach the finish line if you don’t know what you have,” says Holford. With hundreds to thousands of candidate molecules per species, characterizing venom can be a daunting task. And Holford hopes the search for venom drugs can inspire people to protect biodiversity.

“Scientists have identified that we’re going to have a huge loss of biodiversity by 2030, and we’ve only just begun to scratch the surface and identify these poisonous animals,” Holford said. “It’s important to understand not only the therapies these animals give us, but the importance they play in our natural environment.”