Spiders and the sea open new doors to drug discovery

Snakes, marine sponges, tree frogs, centipedes, spiders and deep-sea trenches: these are just some of the areas where scientists are hunting for new drugs.

There is an urgent need for molecules that kill bacteria in new ways. Pursuits through chemical libraries have not delivered, which has encouraged a return to nature. The diversity of life means bags of compounds useful to medicine could await discovery in the strangest of places.

And scientists are willing to dig deep to find them. A research vessel will haul up mud from the ocean floor of the Mid-Atlantic Ridge in January. Next spring, the Atacama Trench, 8,000m down off the coast of Chile, will be scooped for samples. University College Cork is involved in this European project – PharmaSea – seeking novel compounds at sea.

Scientists hope the mud contains unusual bugs that produce unusual chemicals. UCC's Prof Alan Dobson is already testing bacteria returned from deep-sea canyons by the research vessel Celtic Explorer and a remotely operated vehicle (Holland I) to see if they can kill medical miscreants such as drug-resistant E.coli and Staph aureus.

His group is also interested in other sea life, especially bacteria living within deep- sea marine sponges, which can account for 30 per cent of the sponges’ weight. Sponges are known to contain bioactive compounds with anti-cancer and anti-microbial properties. They cannot swim away from predators, so they need chemical defences.

Extreme environments mean novel biology, which in turn could lead to the discovery of new chemical diversity; at least that's what we have found so far, says Prof Marcel Jaspars, the co-ordinator of PharmaSea at the University of Aberdeen.

Jaspars, who trained as a medicinal chemist at Trinity College Dublin, cites cyclosporine as a classic example of the surprises nature can deliver. It was discovered in a fungus on the high plains of Norway in 1969, and its structure was found to be unusual. Tests revealed it had immune suppression abilities. It has since been widely used to prevent organ rejection after transplants.

Jaspars scrutinises for uniqueness the bacteria that Dobson's group isolates. Interesting extracts are sent to partners in Belgium for epilepsy and brain diseases; in Norway for cancer and inflammation; and in Spain for antibiotics.

Poisons and antidotes

Poison is the antidote for a malaise in drug discovery, says Prof Christopher Shaw at Queen's University Belfast. He has sifted through venom from snakes, spiders, scorpions and amphibians for novel drug candidates.

“What’s intriguing about them is that they are infinitely variable,” he says. The venom injected from the fangs of a spider or snake consists of cocktails of compounds, sometimes hundreds of them, each delivering some biological effect.

Shaw has criticised the pharma industry for ignoring this natural repository and persisting with the failed approach of combinatorial chemistry.

As Jaspars explains, combinatorial chemistry is a way of combining small bits of molecules in an almost random fashion to make lots of combinations. “This generates a huge amount of chemistry but a lot of those compounds are not very original. They are based around existing sub-units,” says Jaspars.

“Nature is a great mother of invention,” stresses Shaw, who has been frustrated at the industry’s lack of interest in frog and snake peptides (small proteins). “Drug pipelines have dried up across the world and we are facing the prospect of entering the pre-antibiotic era again.”

But nature has succeeded before. The ACE inhibitor drugs for treating high blood pressure stemmed from the Brazilian pitviper, which uses the molecule to make prey black out through loss of blood pressure. The heila monster spawned a drug for type-two diabetes. Exenatide, a form of a substance found in this lizard’s poisonous saliva, was shown to lead to healthy glucose levels and weight loss.

“These venoms yielded two blockbuster drugs for the developed world. What we hope is to pursue amphibian skin peptides,” says Shaw. Frogs need various antimicrobial defences for their moist skin. There are thousands of these, and it’s time to round up such smart peptides from nature, he adds.

Venoms can be domesticated, and we can take advantage of how precisely targeted they are, says Shaw. Also, venoms often hit targets that are of interest to medicine. Snake venoms, for example, have many molecules that impact the cardiovascular system.

Compounds with morphine-like actions have been discovered in centipedes; the black mamba snake has a compound that blocks pain; and a Seattle company, Kineta, is trialling a drug based on a sea anemone’s sting for auto-immune diseases such as multiple sclerosis.

Drug companies are paying attention to PharmaSea, says Jaspars, and for good reason. There is a treasure trove of useful chemicals for antibiotics and difficult- to-treat conditions such as Alzheimer’s, epilepsy and inflammatory diseases in nature.

STING KINGS: VENOMOUS PAIN RELIEF

Spiders get a bad rap, but they have some fans. Australian scientist Prof Glenn King, for one, believes that spider venom holds potential for critical medicines such as new painkillers.

Venomous animals strike briefly at prey, injecting a blend of bioactive compounds and causing immediate paralysis. This is achieved via compounds that hit proteins in the victim’s neurons and muscle cells, which are vital for basic movement. That is why venoms from snakes, bees, scorpions, marine cone snails, sea anemones and spiders have been attracting scientists.

There are thousands of spider species, so there is a great deal of venom to test for its drug potential. “The key thing is that these animals are generally not toxic to humans, which is why they are a good drug source. Spiders have evolved these peptides for about 400 million years, so they come pre-optimised and have an incredible high affinity for the target,” says King.

King is aiming to develop novel drugs for pain relief and for treating stroke victims. His group at the University of Queensland boasts the largest collection of spider venoms.

He collects venom from spider fairs, where people gather to exchange pet spiders.

“I have a German postdoc who is fairly well connected in that community who goes and samples venoms from the pet collection. It saves us having to go into the wild,” says King.