Small Molecule Inhibitors of the Trimeric Influenza Virus Polymerase
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.[+] Read More
FLUINHIBIT's major objective is the discovery of small molecule inhibitors of influenza polymerase subunit interactions as novel antiviral drug candidates.
FLUINHIBIT will identify inhibitors of the protein-protein interaction between PB1 and PA. Since the N-terminal PA-interaction domain of PB1 is highly conserved, molecules able to block the interaction can be expected to inhibit most, if not all, influenza A strains. The most promising hits will then be optimized and processed into preclinical development.
The viral trimeric polymerase complex is an attractive and novel target for inhibition of viral replication. Due to the high level of conservation among different virus strains, subunit inhibitor compounds will bear a lower risk of resistance development. This may be a big advantage with a rapidly mutating virus.
FLUINHIBIT aims to better prepare for emerging epidemics by providing lead candidates of a new target. This may help to protect the public health in case of an influenza pandemic. Also, the provision of novel lead compounds will improve competitiveness of European Pharmaceutical and Biotech Industry.