Animal venoms: The key to the brain?

All substances must first cross the blood-brain barrier before they can reach the central nervous system: vital nutrients may pass, harmful toxins and pathogenic germs are kept out. The body’s own 'bouncers' at the entrance of the brain, consisting of cells and proteins, perform this crucial function. However, these gatekeepers also prevent medication from entering the brain, explains Markus Muttenthaler. He and his team at the Institute of Biological Chemistry are searching for the fundamentals to treat neurological disorders and to deliberately pass the blood-brain barrier for medication. "More than 98 per cent of promising active ingredients for neurological disorders cannot be used because they are blocked from entering the nervous system and cannot reach their target receptors."

Inspired by the animal kingdom

To trick the brain's security system, the researcher has recently opted for animal venoms and was supported by the 1000 Ideas Program by the Austrian Science Fund (FWF) for particularly original research ideas. "I had the idea when observing animals that target the nervous system of their enemies. Due to their special chemical composition, many animal venoms, such as the scorpion's chlorotoxin or the bee's apamin, can pass the blood-brain barrier," Muttenthaler says, who leads the Neuropeptide Research Lab at the University of Vienna and at the University of Queensland. 

Of spiders, scorpions and cone snails

Here, he tries to decipher the biochemical formulations of animal toxins, which are still largely unknown, and to apply this knowledge to the development of biologically active agents. His second research base in Australia is also home to many venomous species with promising toxins – an El Dorado for the medicinal chemist. But also in the reefs of Papua New Guinea, the Amazon or Borneo, armed with headlamps and pipettes, Markus Muttenthaler and his research team search for new candidate compounds. "Snakes are too fast for me, so I keep my hands off them," he admits, "but cone snails and scorpions are my favourite venomous animals." He has not been bitten yet – "and I want to keep it that way!"

Via blood-brain shuttle to the brain

Spiders, scorpions and cone snails are also highly valued "because of their rich diversity in peptides, i.e. tiny proteins that can rather easily be synthesised in the lab," the scientist explains. Once the relevant peptides have been identified, the jungle substances are rendered non-toxic in the lab without altering the brain transport mechanism. The molecules of the animal poisons are then transformed into so-called blood-brain shuttles that, so to say, transport new active agents into the nervous system.

The bigger, the more selective

"Normally, drugs have a small molecule size, so they can enter the brain. However, this often results in a lack of desired selectivity and unwanted side effects," Muttenthaler explains the crux of the problem with transporting active agents, "With the new shuttles, bigger drugs that are more effective can now enter and thus improve our therapies." The results of this project are particularly relevant for neurological diseases such as Alzheimer's, Parkinson's or strokes. Current therapies cannot yet transport antibodies selectively and efficiently to the brain. 

"There is still a lot to do in this project and the biggest challenge will probably be the path to clinical application," the ambitious researcher suspects. For him, discovering new compounds for medical use is the greatest incentive – "because this way we can help patients in the long term." (hm)