Cornering the market for Southeast Asian gac fruit in the Melbourne suburb of Footscray helped a La Trobe University doctoral student come up with one of the most promising proteins yet in the global quest for new drugs to halt the spread of breast, colon, ovarian and prostate cancer.
Pedro Quimbar, working with colleagues at the La Trobe Institute of Molecular Science (LIMS), the University of Queensland and scientists in Germany, has isolated and improved the action of a special protein called a ‘cyclic peptide’ extracted from gac fruit.
Studies on these circular proteins, almost exclusively found in plants, have shown them to be the most effective natural inhibitors so far of an enzyme that helps the spread of cancer cells. The research was published in a recent issue of the international Journal of Biological Chemistry.
More robust for new drugs
Cyclic peptides provide an exciting new approach for drug development. While most proteins are linear in shape and susceptible to breaking, the circular structure of these peptides makes them more robust and useful for pharmaceutical use.
Professor Marilyn Anderson is Mr Quimbar’s principal supervisor. She says one of the most promising of these cyclic peptides – and the leading candidate for future drug design – has until now been extracted from sunflowers.
A Queensland chemist, Dr Norelle Daly, had created a range of variants of such sunflower peptides and provided them for further study to Professor Anderson’s biochemistry lab at La Trobe.
Pioneering peptide research
‘Pedro set out to test these variants, to find out what parts of the molecule were really important, and to see whether their activity could be improved.’
In the process he decided to look into other lesser-known cyclic peptides –including one extracted from gac fruit.
‘The results have been amazing,’ says, Professor Anderson, a pioneer of cyclic peptide research.
‘Pedro’s study found that the substance extracted from gac fruit was a far more potent inhibitor of the action of cancer cells than that found in sunflowers.’
Potent and specific
However, for the molecule to be useful as a drug it needed to be not only potent enough to inactivate an enzyme called matriptase, a key player in the spread of cancer cells.
It also had to be specific, Professor Anderson explains, so it inflicts as little collateral damage as possible on related ‘good’ enzymes such as trypsin, which are used in the digestive process.
‘The elegant part of his project,’ she says, ‘was that once Pedro had something that inhibited both of these enzymes, he altered it so that it would be more selective for matriptase and not trypsin, because we want to minimise side effects.’
Testing on human cancer cells
Professor Anderson says as a result, the gac fruit peptide now looks like the best candidate for developing future matriptase inhibitors.
While any clinical application is still a long way down the track, Mr Quimbar and his colleagues have already started laboratory tests on human cancer cells, looking initially at colon, prostate and breast cancer.
‘The big achievement,’ she adds, ‘has been in understanding the structures of the molecules so we can design more potent inhibitors.
‘Our work here at LIMS – a centre for one of La Trobe’s new Research Focus Areas into understanding diseases – provides us with a platform for the next step towards possible clinical use.
‘The work of our team, and other research at LIMS, is totally focused on designing molecules to stop the spread of cancer cells’, says Professor Anderson.
Building on decades of success
As leading figures in cyclic peptide research, Professor Anderson and former La Trobe graduate Professor David Craik – now at the Institute for Molecular Bioscience at the University of Queensland – began work on these special proteins during the 1990s after their discovery in Africa.
Professor Anderson says Professor Craik first introduced her to cyclic peptides, the active component in a traditional tea used by African women to accelerate child birth. Their stability during the tea making process provided early clues to the potential of these robust peptides.
‘We were the first to clone a gene that coded for a cyclic peptide from plants,’ she says. ‘Our paper was published in PNAS, the US Proceedings of the National Academy of Science, in 2001 – on 9/11, the day the New York’s twin towers were destroyed.’
As well as Mr Quimbar, Professor Anderson and Dr Kerry Dunse from La Trobe, other researchers involved in the study were Professor Craik and Dr Daly from the University of Queensland and scientists from James Cook University, and Ludwig-Maximilians University hospital in Munich, Germany. – Ernest Raetz