Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide.
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.
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
Yuma
Y
Iwai
Hitoshi
H
Takahashi
Dai
D
Hatakeyama
Kazunori
K
Motoshima
Minoru
M
Ishikawa
Kazuyuki
K
Sugita
Yuichi
Y
Hashimoto
Yuichi
Y
Harada
Shigeyuki
S
Itamura
Takato
T
Odagiri
Masato
M
Tashiro
Yoshihisa
Y
Sei
Kentaro
K
Yamaguchi
Takashi
T
Kuzuhara
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004285:Dogs; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology; D007251:Influenza, Human / Q000188:drug therapy*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013792:Thalidomide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000998:Antiviral Agents; D010797:Phthalimides; D013267:Stilbenes; D013792:Thalidomide; D012321:DNA-Directed RNA Polymerases