BPR2-D2 targeting viral ribonucleoprotein complex-associated function inhibits oseltamivir-resistant influenza viruses

Shin Ru Shih, Jim Tong Horng, Leo L.M. Poon, Tzu Chun Chen, Jiann Yih Yeh, Hsing Pang Hsieh, Sung Nain Tseng, Chiayn Chiang, Wan Ling Li, Yu Sheng Chao, John T.A. Hsu

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Objectives: The emergence of oseltamivir-resistant viruses raised the global threat with regard to influenza virus infection. To develop alternative antiviral agents against influenza virus infection is significant and urgent. Methods: A neutralization test was applied as a screening assay and a plaque reduction assay was used for confirmation. Expression plasmids for viral ribonucleoproteins (RNPs) and a plasmid that allowed expression of a pseudoviral reporter RNA were transfected into cells to investigate the effects of a novel antiviral compound on viral RNA synthesis. Results: BPR2-D2 was identified as a novel inhibitor against influenza virus from a hit obtained from high throughput screening of 20000 or more compounds. BPR2-D2 exhibited an excellent antiviral efficacy for the oseltamivir-resistant virus (EC50 ranging from 0.021 to 0.040 mM). No resistant virus was produced through- out 20 passages in the presence of BPR2-D2, whereas oseltamivir-resistant virus was generated at passage 8 using the same experimental system. A molecular target other than neuraminidase (NA) was found because BPR2-D2 inhibited the synthesis of viral RNA that was driven by influenza viral RNP in a transfection assay. BPR2-D2 also exhibited a broad antiviral spectrum against various strains of influenza A and influenza B viruses. Conclusions: BPR2-D2 was identified as a novel inhibitor of influenza virus. It may target viral RNPs that are responsible for viral RNA synthesis. Targeting different molecules compared with NA allows BPR2-D2 to inhibit oseltamivir-resistant viruses.

Original languageEnglish
Pages (from-to)63-71
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume65
Issue number1
DOIs
Publication statusPublished - 2009 Nov 5

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

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