IDENTIFICATION OF N-HYDROXAMIC ACID AND N-HYDROXYIMIDE COMPOUNDS THATINHIBIT THE INFLUENZA-VIRUS POLYMERASE

The RNA-dependent RNA polymerase of influenza virus transcribes messen ger RNA through a unique cap-scavenging mechanism. The polymerase bind s to the cap structure at the 5' ends of host mRNAs, which are then cl eaved and used as primers for viral mRNA synthesis. In an effort to di scover antiviral compounds against this target, an in-vitro transcript ion assay was utilized to screen a proprietary chemical collection. Re sults of this screening effort identified an N-hydroxamic acid structu re as an inhibitor of the capped RNA-dependent transcriptase activity. Subsequent sub-structure searching and screening based upon this phar macophore identified two related N-hydroxy-imide compounds as specific inhibitors. These compounds were found to inhibit the cap-scavenging mechanism through inhibition of the endonuclease function of the polym erase.