Co-opting nature to make cheaper drugs

By Tim Dean
Monday, 21 March, 2011

Sunflower trypsin inhibitor 1 (SFTI-1) is no ordinary peptide. It features a unique cyclic structure that makes it particularly suited as a peptide drug ‘scaffold.’

As its name suggests SFTI-1 is produced naturally in sunflowers, but now researchers from the University of Queensland have developed a technique to allow other plant species to produce the useful peptide.

This could open up the possibility of mass producing large quantities of SFTI-1, or variants, for a much lower cost than can be achieved by synthesising the peptide.

According to Dr Joshua Mylne from the Institute of Molecular Bioscience and the University of Queensland, SFTI-1 is useful because of its cyclic structure.

“It’s very stable because it has no ends,” he told ALS. “Most peptides have a front and a back, which can be attacked by enzymes. SFTI-1 also has the perfect shape to block proteases.”

Proteases are enzymes that break down proteins, and some are known to be involved in diseases, including cancer.

SFTI-1 is already known to inhibit the epithelial serine protease, matriptase, which is known to cause cancer when misregulated.

However, the SFTI-1 naturally produced in sunflowers also blocks other proteases, including one involved in normal digestion, making it less suitable as a drug.

SFTI-1 can be readily modified by chemical synthesis to target specific proteases, but once a potential drug is found, its large scale production is expensive.

“Although SFTI and related proteins show great promise as drug templates, the cost to manufacture them is a significant barrier to widespread use,” said Mylne.

Far better if it could be modified and then produced in large quantities naturally. And this is precisely what Mylne and his team’s discovery may allow.

They cloned a gene found in sunflowers, PawS1, which is responsible for producing a 151-residue protein, including the 14-residue SFTI-1. They also found a similar gene in another species of sunflower which produced a very similar peptide, SFT-L1, or ‘SFTI-1 Like.’

Because sunflowers are not as conducive to genetic manipulation, the genes were introduced to the model Arabidopsis thaliana, which was then shown to produce SFTI-1, although with lower efficiency than sunflowers.

Using this system the researchers are now exploring how many and where changes in PawS1 can be made so they can produce peptides that inhibit other proteases, such as those involved in other diseases or cancers.

Once drug designers settle on a suitable SFTI-1-like peptide, a correspondingly modified PawS1 gene could be introduced into another species for production, such as safflower, which would make SFTI-1 in its seeds.

“Seeds are an attractive system for the production of pharmaceuticals, as they are cheap to grow and their contents are stable at room temperature, and sterile inside their coat,” said Mylne.

“There are also established systems in place for their production, harvest, storage and transportation, meaning they could be the ultimate low-cost drug delivery system.”

Eventually, large quantities of valuable anti-cancer drugs could be produced using natural machinery in plants.

The research was supported by the Australian Research Council and was published in the journal Nature Chemical Biology today.

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