Released By: Australian Synchrotron
Release Date: Wed 20 August 2008

Lighting the way to a Victoria Prize - and a new era in drug design

Peter Colman, winner of this year's Victoria Prize, says having a synchrotron in Melbourne gives him and his colleagues a home town advantage.

It would have saved him weeks of travel and years of work if it had been available when he and his colleagues developed the anti-flu drug Relenza.

Now Colman is using the Australian Synchrotron to identify drug targets in cancer.

The key discoveries that made Relenza possible were: solving the 3D structure of the flu protein neuraminidase; and recognising that one small part of it never changed.

Both depended on protein crystallography using X-ray diffraction. But it was slow work using the tools available in the early 1980s.

Colman and his colleagues published the structure of neuraminidase in 1983 - five years after the first crystals of the protein were grown by Graeme Laver at ANU in 1978.

"Our very first description of the structure was done using a laboratory source of X-rays," says Colman.

It wasn't until he and his colleague Jose Varghese turned to the more powerful light sources offered by synchrotrons in Germany and Japan that the structure was fully solved in the mid-1980s.

The synchrotron brought speed and volume. The technology to freeze crystals had not yet been developed, so researchers just had to take as many pictures as possible before the crystal dissolved.

"We could collect more data from a single crystal on the synchrotron than in the lab, so there were fewer errors," Colman says.

In those days, the process of accessing the X-ray beamline was very ad hoc, according to Colman.

"We would write to anyone we knew, asking for some time. And all the beamtime was parasitic - it depended on what the physicists were doing."

The structure of neuraminidase provided the researchers with a clear picture of the changes to the protein when the virus underwent its periodic mutations, and they realised there was one tiny cleft in the virus that did not change from mutation to mutation. This was the catalytic site of the protein and it became the target for rational drug design.

With Mark von Itzstein and Wen-Yang Wu, then at the Victorian College of Pharmacy at Monash University, a molecule able to plug the cleft was designed and the first in a new class of drugs -neuraminidase inhibitors - was born.

Zanamivir, also called Relenza, was commercialised by Australian biotech company Biota and its pharmaceutical partner GlaxoSmithKline in the late 1990s.

Colman is still using synchrotron light to drive his research into the structure of proteins.

Since 2001 he has been working at the Walter and Eliza Hall Institute of Medical Research on potential drug targets for cancer therapeutics. Last year the WEHI team announced it had visualised a 'molecular switch' that regulates cell death using the crystallography beamline at the Australian Synchrotron.

Having the synchrotron in the same city as his research has been a welcome change, says Colman. Like all users, he has to apply for access to the beamline through the quarterly allocation system. But he has hometown advantage when there are cancellations from out-of-town scientists, and his team can often get more access at short notice.

And Colman says the way crystallography is done has changed dramatically.

"These days you don't have to be as much of a physicist," he says. "And the level of 'wet' molecular biology is entirely different. I learn just as much from the younger scientists as they learn from me."

The Director of the Australian Synchrotron, Professor Rob Lamb said "We are just beginning to see the enormous benefits that synchrotron science can bring to Australian scientists and their research and Peter Coleman is a great example of this".

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