Identification of BPR3P0128 as an inhibitor of cap-snatching activities of influenza virus

John T.A. Hsu, Jiann Yih Yeh, Ta Jen Lin, Mei Ling Li, Ming Sian Wu, Chung Fan Hsieh, Yao Chieh Chou, Wen Fang Tang, Kean Seng Lau, Hui Chen Hung, Ming Yu Fang, Shengkai Ko, Hsing Pang Hsieh, Jim Tong Horng

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38 Citations (Scopus)

Abstract

The aim of this study was to identify the antiviral mechanism of a novel compound, BPR3P0128. From a large-scale screening of a library of small compounds, BPR3P compounds were found to be potent inhibitors of influenza viral replication in Madin-Darby canine kidney (MDCK) cells. BPR3P0128 exhibited inhibitory activity against both influenza A and B viruses. The 50% inhibitory concentrations were in the range of 51 to 190 nM in MDCK cells, as measured by inhibition-of-cytopathic-effect assays. BPR3P0128 appeared to target the viral replication cycle but had no effect on viral adsorption. The inhibition of capdependent mRNA transcription by BPR3P0128 was more prominent with a concurrent increase in cap-independent cRNA replication in a primer extension assay, suggesting a role of BPR3P0128 in switching transcription to replication. This reduction in mRNA expression resulted from the BPR3P-mediated inhibition of the cap-dependent endoribonuclease (cap-snatching) activities of nuclear extracts containing the influenza virus polymerase complex. No inhibition of binding of 5′ viral RNA to the viral polymerase complex by this compound was detected. BPR3P0128 also effectively inhibited other RNA viruses, such as enterovirus 71 and human rhinovirus, but not DNA viruses, suggesting that BPR3P0128 targets a cellular factor(s) associated with viral PB2 cap-snatching activity. The identification of this factor(s) could help redefine the regulation of viral transcription and replication and thereby provide a potential target for antiviral chemotherapeutics.

Original languageEnglish
Pages (from-to)647-657
Number of pages11
JournalAntimicrobial agents and chemotherapy
Volume56
Issue number2
DOIs
Publication statusPublished - 2012 Feb

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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