Swine-origin influenza A virus has caused pandemics throughout the world and
influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable.
Influenza A expresses an
RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-
influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from
thalidomide (PPT analogs). For this screen we used a PA
endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA
endonuclease activity and retard the growth of
influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of
influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA
endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA
endonuclease assay in the screening of anti-
influenza drugs and are therefore useful for future strategies to develop novel anti-
influenza A drugs and for mapping the function of the
influenza A
RNA polymerase subunits.