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Issue 467, 21 May 2001

Leeds scientists’ success fights deadly handshake of hepatitis C virus

Scientists the world over are racing to unlock the secrets of viral diseases such as hepatitis C, but a dedicated research team at the University of Leeds is the first in Britain to map the atomic structure of the virus polymerase, the part which enables the virus to replicate its genome. In less than two years they have caught up with long-standing research efforts in some of the biggest pharmaceutical companies in the world.

Studying protein – Dr Rachel Trowbridge and Damien O’Farrell

The excellent progress made by the research team means they are closer to finding a possible cure for the disease. Hepatitis C is a major threat to human health throughout the world. Between 400,000 and 500,000 people in the UK carry the virus, many without their knowledge. Described as a viral time bomb, hepatitis C can do serious damage before any symptoms develop. In 85% of cases the disease causes serious liver damage, resulting in cirrhosis or cancer over 20 to 25 years. There is no vaccination and current treatments are effective in only 25% of patients, expensive and not uniformly available, and can cause very serious side-effects with long-term use. The disease is transmitted through contact with infected blood, and many sufferers are former intravenous drug users.

Colour coded - each region has its specific role in replication

Both Dr Joachim Jäger and Professor Rowlands came to Leeds in 1996. Professor Rowlands had been working with hepatitis C in a commercial environment, and was determined to carry on that work in an academic setting.

"I set up the hepatitis C laboratory with Dr Mark Harris when I first came to Leeds," he said. " We’ve put a lot of work into this area, and we now have one of the largest hepatitis research laboratories in the country."

Virus expert – Professor Rowlands

Dr Jäger came to Leeds from Yale University, where he had been working on the atomic structure of the first drugs used to combat AIDS. These drugs are not ‘cures’ but, generally in combination, they inhibit the replication of the virus to prevent the onset of AIDS. At Leeds, working in the Astbury Centre for Structural Molecular Biology alongside Professor Rowlands, Dr Rachel Trowbridge and Damien O’Farrell, he began to use the same approach for the hepatitis C virus (HCV). HCV, like HIV, has to rely on its own replication machinery to produce new copies of its genomic RNA, the viral equivalent of human DNA. Mapping the structure of the polymerase allowed Professor Rowlands, Dr Jäger and their team to see exactly how this might take place.

Dr Jäger’s structure of the HCV polymerase is currently the most detailed image available in the public domain. Like many other related enzymes, the HCV polymerase resembles a loosely balled right hand. ‘Fingers’ and ‘thumb’ form a deep cleft with the active site at the centre of the ‘palm’ domain. The ‘palm’ binds two magnesium ions, both of which are crucial to the creation of new viral RNA molecules. Any small molecule compound that will fit into the palm domain and freeze the movement of the rest of the structure will bring the chemical process of replication to a standstill and is a possible contender as a treatment for hepatitis C. The key is to discover cavities into which the compound might be inserted to block the structure from moving and carrying out its task of replication.

X-ray vision - Dr Joachim Jäger

"The process used to determine the polymerase structure was X-ray crystallography," explains Damien O’Farrell. "Using a large quantity of purified polymerase protein, we had to find the optimum conditions which would turn it into crystalline form and then froze those crystals in liquid nitrogen at incredibly low temperatures. X-ray images of the crystals allowed us gradually to model the polymerase."

Microbiologist Dr Trowbridge joined the University of Leeds in 1998, but has been researching HCV for over ten years. Along with Professor Rowlands and Dr Jäger, she has been looking at the role of specific regions of the polymerase in the replication of the virus. This multidisciplinary approach between molecular microbiology and structural biology has allowed the research to link structure to function.

3D – the polymerase structure

Much of the work to design anti-viral drugs is beyond the resources of an academic research centre. For this reason, Professor Rowlands and Dr Jäger have formed a Leeds Innovations company, Replizyme Ltd which has gone into partnership with Arrow Pharmaceuticals to provide additional resources to carry on the work.

"We’ve made very significant progress in a remarkably short amount of time," said Dr Jäger. "To find a candidate as an anti-viral compound, we’ve been searching through ‘libraries’. Most of the commercial researchers are working with libraries containing up to 800,000 compounds, but we’ve been looking at just 25,000, pre-selected for their low toxicity and ability to be easily absorbed and broken down within the body. Our structure has helped us catch up with some of the bigger companies and other universities which are also researching this area, and already we have several potential anti-viral compounds on the shelf which we are fine-tuning. Our work has caught the attention of others in this field – I’m regularly contacted by other research institutions and pharmaceutical companies who want to know our latest findings."

"Discovering a potential treatment is more than just finding what is effective against HCV. You also have to ensure that drugs which inhibit HCV don’t also stop the natural replication that happens all the time in the human body. The compounds have to be specific to that particular viral polymerase – which is why we need a structure in atomic detail to see the exact shape of the cavities and so find compounds with a perfect fit.

Even if we do identify a suitable compound, the drug itself might still be between seven and ten years from actually being on the market."

It is unlikely that a vaccination will be found for hepatitis C in the near future, as the virus is adept at changing to avoid detection by antibodies. The only hope for sufferers is that drugs will be discovered which keep the disease under control and prevent fatal damage to the liver. The discoveries made by the Leeds researchers about this virus are the first steps along this road, and they may also provide the key to treating other viral diseases in the future.

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