The clock is counting down to the next influenza pandemic. Since 1997, the avian influenza virus strain H5N1 has infected over 250 people worldwide with a fatality rate of ~60%, although so far without sustained human-to-human transmission. In view of the very few efficacious drugs against influenza virus infections and the time it takes to develop a matching vaccine, there is an unmet worldwide need for new anti-influenza drugs. The viral trimeric RNA polymerase complex, consisting of the subunits PA, PB1 and PB2, is an attractive target for inhibition of viral replication. However, due to the absence of detailed structural information and clear understanding of the subunit functions so far, inhibitors of the RNA polymerase developed as drug candidates are extremely scarce. Based on the recent finding that a short peptide corresponding to the PA-binding domain of the PB1 subunit blocks both polymerase activity and viral spread, FLUINHIBIT aims at discovering small molecule inhibitors of this subunit interaction crucial for viral replication. Starting from the 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 fluorescence polarization 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.
Field of science
- /medical and health sciences/basic medicine/medicinal chemistry
- /medical and health sciences/health sciences/infectious disease/RNA virus/influenza
Call for proposal
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Funding SchemeCP-FP - Small or medium-scale focused research project