The 2009 H1N1 pandemic and the ongoing threat of highly pathogenic H5N1 strains have focused attention worldwide on the urgent need for effective anti-influenza drug options when the public is not protected by vaccination. The need is pressing since several circulating strains are resistant to currently stock-piled anti-neuraminidase drugs. In this project, we will exploit our recent advances in the detailed mechanistic understanding of the structure and function of the viral polymerase, the replication machine of the virus, to develop new drug candidates that inhibit viral replication in infected cells. The polymerase is an excellent drug target as it is highly conserved in all influenza A strains, whether of avian, swine or human origin. The project consortium includes 12 academic and SME partners from 6 European countries chosen for their expertise and complementarity. The focused drug design programme will start with already existing patented small molecule hits against two different polymerase active site targets and use structure-based medicinal chemistry expertise to arrive at optimized leads to enter preclinical studies. The aim is to take one preclinical candidate to phase 1 clinical trials, with contingency plans in place to cover setbacks. In parallel, a world-leading network of European academic labs will continue fundamental research on influenza polymerase atomic structure, cellular function and role in inter-species transmission, which will feed back into the drug design programme with enhanced assays for polymerase inhibitors, improved understanding of how the inhibitors work in the cellular context and potential resistance mechanisms, as well as providing new targets for future anti-influenza drug-design. If successful, the project will provide new opportunities to treat both seasonal and pandemic flu and thus can have an enormous impact on world-wide public health and well-being as well as the competitiveness of the European pharmaceutical sector