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Glycobiologist secures funding for collaborative flu research

With the recent emergence of Tamiflu-resistant strains of H1NI swine flu virus, the need to find new treatments against the virus is greater than ever.

Departmental Reader Dr Terry Butters has just received funding to explore whether a potentially new class of anti-viral drugs might help in the fight against flu. US-based biotechnology company Romark, which has already provided 6 months of support to the Biochemistry department researcher, will be investing in a further 3 years.

The different stages of the Drosophila life cycle. Image taken from FlyMove with permission (http://flymove.uni-muenster.de).

Model of the Influenza haemagglutinin protein. The protein is shown in white and blue; the carbohydrate modifications are shown in yellow. By kind permission of Dr Mark Wormald, Glycobiology Institute. - Click to Enlarge.

The class of drugs, known as thiazolides, was developed by Dr Jean-Francois Rossignol, the founder of Romark. Thiazolides are currently being used to treat infectious bacterial enteritis - inflammation of the intestines caused by a bacterial infection.

Dr Rossignol and his colleagues were interested to know whether the drugs might be useful against other microbes. To their surprise, the researchers found that the drugs had anti-viral activity against the H1NI flu virus and other viruses.

"The group suspects that the drugs are affecting viral haemagglutinin, the protein responsible for binding and subsequent fusion of the flu virus with the cell," says Dr Butters.

Haemagglutinin is one of the proteins which sits in the flu virus envelope. It is a glycoprotein - a protein which is modified after it is made by the addition of carbohydrates that are vital to its function.

Thiazolides appear to interfere with the cellular processes that ensure the right carbohydrates are added onto the newly-synthesized protein. As a result, a faulty haemagglutinin protein is made by the host cell, disrupting proper assembly of the virus and exit of the virus from the cell.

The drugs attack the virus at a different step from the anti-flu drugs currently available and could therefore be very important.

'We see it very much as a collaboration. We're building on the expertise we have in identifying mechanisms of action of small molecules and in medicinal chemistry'

Dr Butters' works in the Glycobiology Institute which is headed by Professor Raymond Dwek. His expertise in glycoprotein biology led to him being contacted by Dr Rossignol.

"Dr Rossignol approached our group to see if we could help him find a mechanism of action for thiazolides. If we understand the mechanism better, then we'll be able to improve drug design," explains Dr Butters.

His group works with small molecules that interfere with the cellular processes responsible for glycoprotein production. He is trying to develop these into drugs against the hepatitis C virus which also uses a viral envelope glycoprotein.

If more can be uncovered about how thiazolides work, this may also open up the possibility of using them in combination with compounds Dr Butters' own lab is developing.

"We have a known mechanism of action for our compounds, and our initial experiments suggest that the drug works in a slightly different way. Both interfere with glycoprotein maturation of viral envelope proteins, so we think we are hitting the virus twice."

A 'double hit' approach is an attractive one given the flu virus' potential to mutate and evade drug treatment - the virus is unlikely to acquire mutations that would allow it to get round two different blocks.

Dr Butters is very pleased that Dr Rossignol has chosen to work with his group on the project. "We see it very much as a collaboration. We're building on the expertise we have in identifying mechanisms of action of small molecules and in medicinal chemistry, and looking at the anti-viral arena has been a key activity for many years. It will give us a great insight into how viruses mature."

The Glycobiology Institute's Director Professor Dwek said that he was delighted to help achieve this funding for Dr Butters' group. "It completes the initial phase of the five year plan for the Institute in which it changes the emphasis to be on viruses".

The funding from Romark will support a number of people in the lab including Dr Andrew Stachulski, a chemist who worked with Dr Rossignol in developing thiazolides. He will move from Liverpool to Oxford carry out the work.

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