Fisetin and rutin as 3C protease inhibitors of enterovirus A71

Lin, Ying-Ju; Chang, Yi-Chih; Hsiao, Nai-Wan; Hsieh, J.H.; Wang, Ching-Ying; Kung, Szu Hao; Tsai, Fuu‐Jen; Lan, Yu Ching; Lin, Cheng‐Wen

doi:10.1016/j.jviromet.2012.03.020

Cited by 76 publications

(67 citation statements)

References 36 publications

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“…It has been previously shown that rupintrivir (AG7088) efficiently blocked EV71 replication as a potent 3C proteinase inhibitor (16,25,26). Therefore, we evaluated the antiviral effects of different concentrations of NITD008 with or without rupintrivir by the Gluc-EV71 infection assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 M and a 50% cytotoxic concentration of 119.97 M. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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“…The induction expression and purification of E. coli-synthesized ORF6 protein were performed as described in our prior reports. 10,11 Finally, the recombinant ORF6 protein was purified using immobilized-metal affinity chromatography as described in our previous study, 12 and then analyzed by Western blotting with anti-His-tag monoclonal antibody and alkaline phosphatase-conjugated goat antimouse immunoglobulin G (IgG) antibodies. The immunoreactive band was developed with tetranitroblue tetrazolium/5-bromo-4-chloro-3-idolylphosphate (TNBT/BCIP) (Gibco, Invitrogen, Merelbeke, Belgium) (Invitrogen).…”

Section: Construction and Expression Of Recombinantorf6 Protein In Esmentioning

confidence: 99%

Phage display technique identifies the interaction of severe acute respiratory syndrome coronavirus open reading frame 6 protein with nuclear pore complex interacting protein NPIPB3 in modulating Type I interferon antagonism

Huang¹,

Lee²,

Lin³

et al. 2017

Journal of Microbiology, Immunology and Infection

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“…18) Several geranyl-substituted flavanones that were isolated from P. tomentosa as minor components showed inhibitory activity against papain-like protease of coronavirus of severe acute respiratory syndrome (SARS). 19) As polyphenolic compounds, the activity of flavonoids is commonly attributed to their antioxidant, anti-inflammatory activities.…”

Section: )mentioning

confidence: 99%

Antiviral Activity of Paulownia tomentosa against Enterovirus 71 of Hand, Foot, and Mouth Disease

Chen

et al. 2015

Biological ^|^ Pharmaceutical Bulletin

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The bark, leaves, and flowers of Paulownia trees have been used in traditional Chinese medicine to treat infectious and inflammatory diseases. We investigated the antiviral effects of Paulownia tomentosa flowers, an herbal medicine used in some provinces of P. R. China for the treatment of skin rashes and blisters. Dried flowers of P. tomentosa were extracted with methanol and tested for antiviral activity against enterovirus 71 (EV71) and coxsackievirus A16 (CAV16), the predominant etiologic agents of hand, foot, and mouth disease in P. R. China. The extract inhibited EV71 infection, although no effect was detected against CAV16 infection. Bioactivity-guided fractionation was performed to identify apigenin as an active component of the flowers. The EC 50 value for apigenin to block EV71 infection was 11.0 µM, with a selectivity index of approximately 9.3. Although it is a common dietary flavonoid, only apigenin, and not similar compounds like naringenin and quercetin, were active against EV71 infection. As an RNA virus, the genome of EV71 has an internal ribosome entry site that interacts with heterogeneous nuclear ribonucleoproteins (hnRNPs) and regulates viral translation. Cross-linking followed by immunoprecipitation and reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that EV71 RNA was associated with hnRNPs A1 and A2. Apigenin treatment disrupted this association, indicating that apigenin suppressed EV71 replication through a novel mechanism by targeting the trans-acting factors. This study therefore validates the effects of Paulownia against EV71 infection. It also yielded mechanistic insights on apigenin as an active compound for the antiviral activity of P. tomentosa against EV71 infection.

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Fisetin and rutin as 3C protease inhibitors of enterovirus A71

Cited by 76 publications

References 36 publications

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Phage display technique identifies the interaction of severe acute respiratory syndrome coronavirus open reading frame 6 protein with nuclear pore complex interacting protein NPIPB3 in modulating Type I interferon antagonism

Antiviral Activity of Paulownia tomentosa against Enterovirus 71 of Hand, Foot, and Mouth Disease

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