There is a need to develop new anti-influenza agents due to limitations and viral resistance to current influenza treatments. Influenza RNA-dependent RNA polymerase (RdRp), which consists of three subunits (PA, PB1 and PB2), is necessary for virus transcription and is a promising target for the development of inhibitors. To facilitate the discovery of new RdRp inhibitors targeting the PA subunit, we have developed a fluorescent polarization binding assay to screen fragments and analyze follow-up targeted libraries for SAR purposes. High affinity compounds that exhibited no cellular cytotoxicity were found to inhibit viral plaque formation (IC50 = 12-18 �M) compared to a Merck PA inhibitor (IC50 = 3 �M). Evaluation of ADME properties of our initial inhibitors along with insight provided from inhibitor-protein co-crystal structures directed structural alterations which resulted in the generation of compounds with superior ADME properties and higher plaque inhibition efficacy.

Identification and evaluation of influenza RNA-dependent RNA polymerase (RdRp) inhibitors

244th National Meeting (2012)

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