Identification of N-Hydroxamic Acid and N-Hydroxyimide Compounds that Inhibit the Influenza Virus Polymerase

The RNA-dependent RNA polymerase of influenza virus transcribes messenger RNA through a unique cap-scavenging mechanism. The polymerase binds to the cap structure at the 5′ ends of host mRNAs, which are then cleaved and used as primers for viral mRNA synthesis. In an effort to discover antiviral compounds against this target, an in-vitro transcription assay was utilized to screen a proprietary chemical collection. Results of this screening effort identified an N-hydroxamic acid structure as an inhibitor of the capped RNA-dependent transcriptase activity. Subsequent sub-structure searching and screening based upon this pharmacophore identified two related N-hydroxyimide compounds as specific inhibitors. These compounds were found to inhibit the cap-scavenging mechanism through inhibition of the endonuclease function of the polymerase.