Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide

Yuma Iwai, Hitoshi Takahashi, Dai Hatakeyama, Kazunori Motoshima, Minoru Ishikawa, Kazuyuki Sugita, Yuichi Hashimoto, Yuichi Harada, Shigeyuki Itamura, Takato Odagiri, Masato Tashiro, Yoshihisa Sei, Kentaro Yamaguchi, Takashi Kuzuhara

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5379-5390
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number14
DOIs
Publication statusPublished - 2010 Jul 15
Externally publishedYes

Keywords

  • Endonuclease
  • Influenza
  • Phenethylphenylphthalimide
  • RNA polymerase
  • Thalidomide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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