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Harnessing nature’s vast array of venoms for drug discovery

There are lessons to be learned from venoms.

Scorpions, snakes, snails, frogs and other creatures are thought to produce tens or even hundreds of millions of distinct venoms. These venoms have been honed to strike specific targets in the body.

For victims of a scorpion’s sting, that spells doom. For scientists, however, the potent molecules in venoms hold the potential to be adapted into medicines. But venoms are difficult to isolate and analyze using traditional methods, so only a handful have been turned into drugs.

Now a team led by scientists at The Scripps Research Institute (TSRI) has invented a method for rapidly identifying venoms that strike a specific target in the body – and optimizing such venoms for therapeutic use.

The researchers demonstrated the new method by using it to identify venoms that block a certain protein on T cells – a protein implicated in multiple sclerosis, rheumatoid arthritis and other inflammatory disorders. The researchers then used their method to find an optimized, long-acting variant of a venom that blocks this protein and showed that the new molecule powerfully reduces inflammation in mice.

“Until now we haven’t had a way to seriously harness venoms’ vast therapeutic potential,” said principal investigator Richard A. Lerner, Lita Annenberg Hazen Professor of Immunochemistry at TSRI.

The report on the advance by Lerner and his colleagues was selected as a “Hot Paper” and cover story by the journal Angewandte Chemie.

Choose Your Poison

The use of venoms as therapies may seem paradoxical, since these molecules generally evolved to harm and kill other organisms. But a low dose delivered to the right place can sometimes have highly beneficial effects. The pain-killing drug ziconotide (Prialt®), for example, is derived from one of the venoms used by cone-snails to immobilize their fishy prey. Venoms also are attractive from a drug development perspective because they tend to hit their targets on cells with very high potency and selectivity.

Drug companies would have adapted far more venoms into therapies by now, but the traditional method of determining the biological target of a venom is slow, difficult and expensive. It involves the extraction of relatively large quantities of venom from the animal species in question, followed by purification of the molecules and laborious lab-dish tests to see how they affect cells.

The new method is geared for speed and involves the extraction only of information – with little direct involvement of venomous creatures. To start, the TSRI-led team, including first author Hongkai Zhang, a senior scientist in the Lerner laboratory, consulted animal toxin databases and assembled a list of 589 venoms whose protein sequences have features of interest. They then synthesized the venoms’ genes and inserted them into special viruses that deliver genes into cells.