Synchrotron becoming drug design essential, say researchers

CSIRO structural biologist Jose Varghese believes that synchrotrons are essential tools for finding out how proteins work, and designing drugs to specifically interact with them.

"When you're designing drugs, it's like getting a piece to fit in a jigsaw puzzle, you can't have an approximate fit," he says.

A synchrotron in Australia will expedite research into protein structure and function, Varghese explains, by allowing researchers to precisely see how proteins interact with each other and with small molecules.

"The genome will tell us a lot, but really what makes us tick are the gene products," he says.

Varghese and his collaborators, led by Prof Richard Simpson at the Joint Proteomics Laboratory at the Ludwig Institute for Cancer Research and Royal Melbourne Hospital (part of the CRC for Cellular Growth Factors), have just published a paper in the Proceedings of the National Academy of Science describing the structure of the interleukin-6 (IL-6) receptor, a key piece of the puzzle in one of the major inflammatory signalling pathways.

The structure was determined using X-ray crystallography, and the Australian scientists used a synchrotron in Chicago to get the data.

When the IL-6 receptor binds IL-6, it forms a complex with gp130, a signalling protein that sets off the JAK/Stat signalling pathway in the cell. While this is an important inflammatory mechanism, inappropriate signalling through the IL-6 receptor has been linked to autoimmune diseases including rheumatoid arthritis, cancers including multiple myeloma and prostate cancer and even cardiovascular disease.

The IL-6 receptor structure will be a key tool in the development of therapeutics targeted at the IL-6 signalling pathway, says Varghese.

The team has been working on the structure of the receptor for a number of years, hampered by the difficulties encountered in producing the protein in a form suitable for crystallisation.

"Our competitive edge is to look at difficult problems," Varghese says.

While the structure provides valuable information about the receptor and the complex it forms, Varghese is also interested in using the existing structure as a template for small molecule inhibitors, targeting the binding site of IL-6 to the receptor.

"If we design inhibitors to block the first event, we can block the entire signalling cascade," he said. "It would also be useful for teasing out the biochemical pathways."

Varghese and his team are using Caduceus, a powerful 64-node computer, to perform in silico screening of potential small molecule inhibitors for the IL-6 receptor. But commercialisation of any inhibitors is still a long way off, he says.

"We're talking long-term. I was involved in the development of Relenza [the influenza drug commercialised by Biota] and that took years," Varghese says.