Identification of a novel compound with antiviral activity against influenza A virus depending on PA subunit of viral RNA polymerase

Kazunori Yamada, Hiroko Koyama, Kyoji Hagiwara, Atsushi Ueda, Yutaka Sasaki, Shin nosuke Kanesashi, Ryuki Ueno, Hironori K. Nakamura, Kazuo Kuwata, Kazufumi Shimizu, Masaaki Suzuki, Yoko Aida

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Influenza viruses have developed resistance to current drugs, creating a need for new antiviral targets and new drugs to treat influenza virus infections. In this study, computational and experimental screening of an extensive compound library identified THC19, which was able to suppress influenza virus replication. This compound had no cytotoxic effects and did not disrupt cell cycle progression or induce apoptosis in MDCK cells as confirmed by WST-1 assays, flow cytometry analysis, and caspase-3 assays. Time-of-addition experiments showed that THC19 acts at a relatively early stage of the viral lifecycle. Subsequent mini-genome assays revealed that THC19 inhibited viral genome replication and/or transcription, suggesting that it interferes with one or more of the viral components that form the ribonucleoprotein complexes, namely polymerase basic 2 (PB2), polymerase basic 1 (PB1), polymerase acidic (PA), nucleoprotein (NP) and viral RNA. Finally, mini-genome assays where PB2, PB1, PA or NP from A/WSN/33 (H1N1) virus were replaced with those from A/Udorn/307/1972 (H3N2) virus effectively demonstrated that THC19 inhibited viral multiplication in a manner dependent upon the PA subunit. Taken together, these results suggest that influenza virus PA protein is a potential target for, and may aid the development of, novel compounds that inhibit influenza A virus replication.

Original languageEnglish
Pages (from-to)740-747
Number of pages8
JournalMicrobes and Infection
Volume14
Issue number9
DOIs
Publication statusPublished - 2012 Aug
Externally publishedYes

Keywords

  • Antiviral agents
  • Influenza a virus
  • Mini-genome assay
  • Polymerase acidic (PA)

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Infectious Diseases

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