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

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

doi:10.1093/jac/dkp393

Cited by 24 publications

(23 citation statements)

References 39 publications

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“…The most potent compound, BPR3P0128, was identified biochemically as having potent anti-cap-snatching activity, and its chemical structure was distinct from that of two compounds identified previously in this screening ( Fig. 1) (52,53,62) and two other viral polymerase inhibitors, T-705 (favipiravir) and compound A3 (19,27). Here, we characterized BPR3P0128 and identified its underlying antiviral mechanism.…”

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confidence: 80%

“…We conducted a drugscreening study using a large-scale anti-influenza virus cell-based assay based on the inhibition of the virally induced cytopathic effect (CPE) (52,53,62). An initial hit, CSV0C019002, with a 50% effective (inhibitory) concentration (EC 50 ) of 4.27 M toward A/WSN/33 was identified after screening 20,800 randomly selected small compounds (molecular masses, Ͻ500 Da) from a library.…”

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confidence: 99%

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Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Hsu

Yeh

Lin

et al. 2012

Antimicrob Agents Chemother

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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 MadinDarby 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.

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confidence: 80%

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confidence: 99%

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Hsu

Yeh

Lin

et al. 2012

Antimicrob Agents Chemother

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“…The clinical influenza strains listed in Table 1 were from Clinical Virology Laboratory of Chang Gung Memorial Hospital, Taiwan. Influenza viruses and enteroviruses were propagated using MDCK and RD cells, respectively, and viral titers were determined with a plaque assay (Wong et al, 2005;Shih et al, 2010). The PI3K inhibitor LY294002 was purchased from Sigma (St Louis, MO).…”

Section: Cell Culture Viruses and Reagentsmentioning

confidence: 99%

“…b IC50 was determined by a neutralization assay. c Clinically oseltamivir-resistant strains (Shih et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export

Yen

Chang

et al. 2011

Journal of Ethnopharmacology

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“…Previously, a coumarin derivative, identified originally from screening of at least 20,000 compounds for inhibitors of influenza virus (60), was later found to be effective in inhibiting HIV-1 replication, likely through interfering with Tat-mediated transactivation by our laboratory. An in vitro cell-based screening system, LTR-luciferase reporter system, was established to screen for a series of 291 coumarin derivatives, synthesized by H.-P. Hsieh's group, and 84 of these compounds were found to inhibit more than 80% of Tat transactivity at the concentration of 0.1 M yet had insignificant cytotoxicity to cells.…”

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Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Lin

et al. 2011

J Virol

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The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC 50 ) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection.

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

Abstract: 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.

Cited by 24 publications

References 39 publications

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

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