Structure–activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities

Liu, Ailin; Wang, Haidi; Lee, Simon Ming‐Yuen; Wang, Ying; Du, Guanhua

doi:10.1016/j.bmc.2008.06.049

Cited by 208 publications

(112 citation statements)

References 19 publications

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“…Next, we tested the cytotoxicity of the test compounds, as well as known antiinfluenza drugs as a reference, in a panel of cell lines. Ribavirin (RBV) and oseltamivir showed CC 50 (concentration that causes a decrease of cell viability of 50%) values >250 μM in all tested cell lines (Table S2), as previously reported (23,24). Compound 12 exhibited elevated cytotoxicity; thus it was excluded from further analysis.…”

Section: Resultsmentioning

confidence: 71%

Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase

Muratore

Goracci²,

Mercorelli³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

219

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Influenza viruses are the cause of yearly epidemics and occasional pandemics that represent a significant challenge to public health. Current control strategies are imperfect and there is an unmet need for new antiviral therapies. Here, we report the identification of small molecule compounds able to effectively and specifically inhibit growth of influenza A and B viruses in cultured cells through targeting an assembly interface of the viral RNA-dependent RNA polymerase. Using an existing crystal structure of the primary protein–protein interface between the PB1 and PA subunits of the influenza A virus polymerase, we conducted an in silico screen to identify potential small molecule inhibitors. Selected compounds were then screened for their ability to inhibit the interaction between PB1 and PA in vitro using an ELISA-based assay and in cells, to inhibit nuclear import of a binary PB1–PA complex as well as transcription by the full viral ribonucleoprotein complex. Two compounds emerged as effective inhibitors with IC 50 values in the low micromolar range and negligible cytotoxicity. Of these, one compound also acted as a potent replication inhibitor of a variety of influenza A virus strains in Madin-Darby canine kidney (MDCK) cells, including H3N2 and H1N1 seasonal and 2009 pandemic strains. Importantly, this included an oseltamivir-resistant isolate. Furthermore, potent inhibition of influenza B viruses but not other RNA or DNA viruses was seen. Overall, these compounds provide a foundation for the development of a new generation of therapeutic agents exhibiting high specificity to influenza A and B viruses.

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Section: Resultsmentioning

confidence: 71%

Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase

Muratore

Goracci²,

Mercorelli³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

219

View full text Add to dashboard Cite

show abstract

“…Many reports in the literature describe neuraminidase inhibitor assays relying on the cumbersome use of the influenza virus preparations 1,[8][9][10][11][12] . This procedure is risky, costly and inconvenient for the set-up of a screening assay.…”

Section: Research Articlementioning

confidence: 99%

A screening assay for neuraminidase inhibitors using neuraminidases N1 and N3 from a baculovirus expression system

Kongkamnerd

Milani

Cattoli

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…11,12) This is because NA inhibitors from natural plants as these can be readily applied to neutraceutics for the prevention of virus infection. For instance, our previously reported that polyphenols derived from Rhodiola rosea 13) and Glycyrrhiza uralensis 14) exhibit potent NA-inhibitory activity and Du and co-workers 15) suggested the order of potency for NA inhibition in flavonoids. A recent study reported that sappanchalcone (1) and brazilin (12) …”

mentioning

confidence: 99%

Homoisoflavonoids from <i>Caesalpinia sappan</i> Displaying Viral Neuraminidases Inhibition

Jeong

Kim

et al. 2012

Biological & Pharmaceutical Bulletin

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In this study, twelve neuraminidase (NA) inhibitory compounds 1-12 were isolated from heartwood of Caesalpinia sappan on the basis of their biological activities against three types of viral NAs. Of isolated homoisoflavonoids, sappanone A (2) showed the most potent NAs inhibitory activities with IC 50 values of 0.7 µM [H1N1], 1.1 µM [H3N2], and 1.0 µM [H9N2], respectively, whereas saturated homoisoflavonoid (3) did not show significantly inhibition. This result revealed that α,β-unsaturated carbonyl group in A-ring was the key requirements for viral NAs inhibitory activity. In our enzyme kinetic study, all NA inhibitors screened were found to be reversible noncompetitive types.

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Structure–activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities

Cited by 208 publications

References 19 publications

Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase

Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase

A screening assay for neuraminidase inhibitors using neuraminidases N1 and N3 from a baculovirus expression system

Homoisoflavonoids from <i>Caesalpinia sappan</i> Displaying Viral Neuraminidases Inhibition

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