stilbenes and Orthomyxoviridae-Infections

The anti-influenza virus activities of 50 resveratrol (RV: 3, 5, 4'-trihydroxy-trans-stilbene) derivatives were evaluated using a neuraminidase (NA) activity assay. The results showed that 35 compounds exerted an inhibitory effect on the NA activity of the influenza virus strain A/PR/8/34 (H1N1) with 50% inhibitory concentration (IC50) values ranging from 3.56 to 186.1 μm. Next, the 35 RV derivatives were used to develop 3D quantitative structure-activity relationship (3D QSAR) models for understanding the chemical-biological interactions governing their activities against NA. The comparative molecular field analysis (CoMFA r2=0.973, q2=0.620, qtest2=0.661) and the comparative molecular similarity indices analysis (CoMSIA r2=0.956, q2=0.610, qtest2=0.531) were applied. Afterward, molecular docking was performed to study the molecular interactions between the RV derivatives and NA. Finally, a cytopathic effect (CPE) reduction assay was used to evaluate the antiviral effects of the RV derivatives in vitro. Time-of-addition studies demonstrated that the RV derivatives might have a direct effect on viral particle infectivity. Our results indicate that the RV derivatives are potentially useful antiviral compounds for new drug design and development for influenza treatment.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; Drug Design; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Molecular Docking Simulation; Neuraminidase; Orthomyxoviridae Infections; Quantitative Structure-Activity Relationship; Resveratrol; Stilbenes

Swine-origin influenza A virus has caused pandemics throughout the world and influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable. Influenza A expresses an RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from thalidomide (PPT analogs). For this screen we used a PA endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA endonuclease activity and retard the growth of influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA endonuclease assay in the screening of anti-influenza drugs and are therefore useful for future strategies to develop novel anti-influenza A drugs and for mapping the function of the influenza A RNA polymerase subunits.

Topics: Animals; Antiviral Agents; Cell Line; DNA-Directed RNA Polymerases; Dogs; Humans; Influenza A virus; Influenza, Human; Orthomyxoviridae Infections; Phthalimides; Stilbenes; Thalidomide

The anti-influenza viral activities of six stilbenoids from the lianas of Gnetum pendulum C. Y. Cheng were evaluated with two different assays, neuraminidase (NA) activity assay and cytopathic effect (CPE) reduction assay. The NA assay results showed that all six stilbenoids exerted an NA inhibitory effect, while the CPE assay indicated that among them, isorhapontigenin (2), gnetupendin B (3), shegansu B (4), and gnetin D 6) exhibit significant in vitro anti-influenza viral activity in MDCK cells, with IC(50) values from 0.67 to 11.99 µg/mL in comparison to the positive controls oseltamivir acid and ribavirin whose IC(50) values were 0.040 and 5.54 µg/mL, respectively.

Topics: Animals; Antiviral Agents; Cell Line; Cytopathogenic Effect, Viral; Dogs; Gnetum; Influenza A Virus, H1N1 Subtype; Neuraminidase; Orthomyxoviridae Infections; Phytotherapy; Plant Extracts; Plant Stems; Stilbenes; Viral Proteins

We have previously shown that the life cycles of several viruses are influenced by host-cell redox states. Reports of the antioxidant activities of the plant polyphenol resveratrol (RV) prompted us to investigate its effects on influenza virus replication in vitro and in vivo. We found that RV strongly inhibited the replication of influenza virus in MDCK cells but that this activity was not directly related to glutathione-mediated antioxidant activity. Rather, it involved the blockade of the nuclear-cytoplasmic translocation of viral ribonucleoproteins and reduced expression of late viral proteins seemingly related to the inhibition of protein kinase C activity and its dependent pathways. RV also significantly improved survival and decreased pulmonary viral titers in influenza virus-infected mice. No toxic effects were observed in vitro or in vivo. That RV acts by inhibiting a cellular, rather than a viral, function suggests that it could be a particularly valuable anti-influenza drug.

Topics: Animals; Cell Line; Enzyme Inhibitors; Female; Gene Expression; Influenza A virus; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Oxidation-Reduction; Resveratrol; Stilbenes; Viral Proteins; Virus Replication