Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5

In search of novel targets for influenza inhibitors, a site on PB1 was selected for its high conservation and probable interaction with a host protein, RanBP5, that is key to nuclear import of PB1, where it complexes with PB2, PA, and NP to transcribe viral RNA. Docking with libraries of drug-like compounds led to a selection of five candidates that bound tightly and with a pose likely to inhibit protein binding. These were purchased and tested in vitro, found to be active, and then one was synthetically expanded to explore the structure-activity relationship. The top candidates had a carboxylic acid converted to an ester and electron-withdrawing substituents added to a phenyl group in the original structure. Resistance was slow to develop, but cytotoxicity was moderately high. Nuclear localization of PB1 and in vitro polymerase activity were both strongly inhibited.