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Biology, Target Search and Drug Discovery

Small Molecule Inhibitors of the Trimeric Influenza Virus Polymerase

EC contribution
: € 1.484.250
: 24 months
Starting date
: 01/04/2008
Funding scheme
: Collaborative project - Small- or medium-scale focused research project
: influenza virus polymerase, novel target, subunit interaction inhibitor, high- throughput screening
Contract/Grant agreement number
: HEALTH-F3-2008-201634
Project web-site


FLUINHIBIT aims at discovering small molecule inhibitors of the influenza virus A subunit interaction between PA and PB1, crucial for viral replication.

Starting from an inhibitory peptide, and supported by characterization of the PB1-binding domain of PA, molecular modeling will be employed to rationally design and synthesize peptidomimetics via traditional medicinal chemistry and a novel fragment based library synthesis approach. In parallel, a high-throughput assay will be developed to screen large compound collections and unique in-house small molecule libraries. The resulting hits will be profiled in cell-based assays and lead candidates with antiviral activity will be identified for preclinical development.


Influenza is a highly contagious acute viral infection, which causes annual epidemics as well as recurring devastating pandemics.

Due to its ability to rapidly mutate its genome, influenza A virus is capable of causing worldwide pandemics. Over the past century, mankind has relied mainly on vaccination in the fight against viral pathogens. As a consequence, very few antiviral drugs are available to date. Of the two classes of drugs specific for influenza, the oldest and most affordable drugs face several problems, e.g. development of resistance, safety in pregnant women, reduced dose in elderly patients and the need of close clinical monitoring in certain patient groups. The second and newer class, the neuraminidase (NA) inhibitors, have a better safety profile but their price and limited supply are major constraints for world wide use. In addition, the development of resistance to NA inhibitors has been reported. Nonetheless, antiviral drugs have important roles to play at the start and in the course of a pandemic. In the absence of vaccines during the first wave of infections, antivirals will be the only medical intervention for providing both protection against disease and therapeutic benefit in diseased persons. Thus, the development of novel, more effective therapeutic approaches to inhibit the replication of the influenza virus is of utmost importance and urgency.

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