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Small Molecule Inhibitors of the Trimeric Influenza Virus Polymerase Complex

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Stopping influenza in its tracks

Most people are familiar with the symptoms of influenza, a highly infectious disease that causes annual epidemics. The virus is also responsible for recurring pandemics that can sweep the world with deadly effect.


Mankind's main weapon in its fight against the flu has been the use of vaccines, which cause the body's immune system to 'recognise' and destroy the invading pathogen. One result of the reliance on vaccines has been the limited availability of antiviral drugs, which inhibit the development of the virus rather than destroy it. Designing safe and effective antiviral drugs is difficult as the virus employs the host's own cells to replicate itself. The challenge, therefore, has been to design a drug that can interfere with the virus without also harming the host's cells. Two classes of drugs have a mitigating effect on influenza. The oldest and cheapest group face problems regarding safety in pregnant women, reduced doses for the elderly and the close monitoring of some patients. An additional problem is the development of resistance by the pathogen to the drug. The second and more recent class of drugs are the neuraminidase (NA) inhibitors that, although considered safer, are more expensive and less freely available. Furthermore, scientists have identified the rapid development of resistance by pathogens to NA inhibitors. Thus there is now an urgent need for new and more effective therapies for inhibiting the replication of the influenza virus. The 'Small molecule inhibitors of the trimeric influenza virus polymerase complex' (Fluinhibit) project developed new ground-breaking techniques for combating the influenza virus. The EU-funded project's main goal was to identify small molecules that inhibit the action of the polymerase enzyme in influenza and determine their suitability as new antiviral drugs. Limited interaction among virus strains points to inhibitors being less of a risk for developing resistance than traditional therapies. This is a major advantage when dealing with a rapidly mutating virus such as influenza. A high-throughput technique for screening large chemical libraries was developed by project partners and the results were analysed using cell-based assays. The lead candidates against human and avian influenza strains were identified and will in the future undergo preclinical development. The results of the Fluinhibit consortium will help to prevent an influenza epidemic and lessen the risk of the virus developing resistance to new therapies, thereby protecting the heath and lives of EU citizens.

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