Bulletin

Issue: January/February 2006

News

Milestone in quest for new anti-fungal drugs

La Trobe University researchers have passed a ‘significant milestone’ on the road leading to new anti-fungal drugs – after seven years of solid scientific laboratory effort.

For the first time they have synthesised a compound called Petriellin A, a peptide known to have anti-fungal properties.

‘Petriellin A may have properties which could lead to new anti-fungal drugs to treat immune-compromised patients such as those with HIV/AIDS, transplant patients, and some cancers. These patients have depressed immune systems and are prime targets for systemic fungal infections,’ says team leader Dr Andrew Hughes, Associate Professor and Reader in La Trobe’s School of Molecular Science.

‘But because it took about seven months by conventional methods to produce a tiny amount of Petriellin A by culturing it in the laboratory, and further time to purify it, it really was not a practical proposition as a source of the natural product for our research,’ Dr Hughes said.

‘We passed our milestone recently when PhD student Ms Marianne Sleebs completed a solid phase synthesis – a laboratory process by which significant quantities of synthesised Petriellin A can be ‘manufactured’ in the laboratory in under two weeks.

Basically, this means now we can make and also change it. This in turn means we can test various permutations or analogues of the structure as potential clinical anti-fungal drugs. We don’t pretend that this will happen tomorrow but the road is now open for much more significant testing to take place,’ Dr Hughes said.

Ms Sleebs said she developed the method to synthesise Petriellin A, which involved solid phase strategies and special coupling reagents, by seeking paths which differed from the conventional process.

‘Essentially this means that instead of producing Petriellin A the conventional way in a solution, a long, slow and involved process, I succeeded in developing a way to do it using a solid resin.

‘Petriellin A is a highly modified peptide because it is N-methylated and it cannot be synthesised easily by conventional automated methods. By using my method, it was synthesised and this process can be scaled up,’ Ms Sleebs said.

While developing the new technique Ms Sleebs worked in conjunction with the company Peptide Solutions on La Trobe University’s Research & Development Park.

Peptide Solutions played critical roles in the solid phase synthesis strategy and final deprotection conditions and purification of the Petriellin A.

‘Dr Denis Scanlon and Mr John Karas from the company were fantastic collaborators, providing access to equipment and instruction on the subtle techniques required for the solid phase synthesis of this difficult peptide,’ said
Ms Sleebs.

The current success followed work that began seven years ago when Honours, and later PhD student, Luigi Aurelio, working with Professor Bob Brownlee and Dr Andrew Hughes, first isolated Petriellin A and in collaboration with PhD student, Jason Dang set about determining its
3-D shape.

Dr Hughes said that the medical profession needed more anti-fungal drugs which operated in new ways. ‘Bugs continually work on ways to resist drugs and often succeed. Drugs that operate in new ways have an advantage because

Dr Hughes said that the medical profession needed more anti-fungal drugs which operated in new ways. ‘Bugs continually work on ways to resist drugs and often succeed. Drugs that operate in new ways have an advantage because the bugs have not developed strategies to resist them.

‘Drugs developed from Petriellin A may be able to deal with systemic infections in a different way. Now that Marianne has got us across the synthetic line we can begin the first steps in “drug discovery” – literally making drugs that are effective in new ways,’ he said.

Dr Hughes and Ms Sleebs are currently preparing a paper on their research for publication in an international journal.