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Antiviral Research (v.68, #1)
Antiviral activity and mode of action of caffeoylquinic acids from Schefflera heptaphylla (L.) Frodin by Yaolan Li; Paul P.H. But; Vincent E.C. Ooi (pp. 1-9).
Schefflera heptaphylla is a popular medicinal plant in southern China. Three caffeoylquinic acid derivatives, namely 3,4-di- O-caffeoylquinic acid, 3,5-di- O-caffeoylquinic acid, and 3- O-caffeoylquinic acid, were isolated from this plant and investigated for their antiviral activity against respiratory syncytial virus (RSV). 3,4-Di- O-caffeoylquinic acid and 3,5-di- O-caffeoylquinic acid possessed potent anti-RSV activity. The median inhibitory concentrations (IC50) of 3,4-di- O-caffeoylquinic acid and 3,5-di- O-caffeoylquinic acid against RSV were 2.33μM (1.2μg/ml) and 1.16μM (0.6μg/ml), respectively, in a plaque reduction assay. The dicaffeoylquinic acids exhibited minimal cytotoxicity against HEp-2 cells with median cytotoxic concentration (CC50) higher than 1000μM. The maximal non-cytotoxic concentration (MNCC) of the two dicaffeoylquinic acids were about 96.7μM, which suggested their anti-RSV effect was not due to cytotoxicity. The antiviral action of 3,4-di- O-caffeoylquinic acid and 3,5-di- O-caffeoylquinic acid was specific against RSV, as they had no obvious antiviral activity against influenza A (Flu A), Coxsackie B3 (Cox B3), and Herpes simplex type one (HSV-1) viruses. Studies were performed that indicated that the dicaffeoylquinic acids could inhibit RSV directly, extracellularly, but only at much higher concentrations than seen in standard assays. Moreover, they could not inhibit RSV attachment to host cells, and could not protect HEp-2 cells from RSV infection at lower concentrations. The data suggest that the compounds exerted their anti-RSV effects via the inhibition of virus–cell fusion in the early stage, and the inhibition of cell–cell fusion at the end of the RSV replication cycle.
Keywords: Schefflera heptaphylla; Dicaffeoylquinic acids; Antiviral activity; RSV
In vitro and in vivo influenza virus-inhibitory effects of viramidine by Robert W. Sidwell; K.W. Bailey; M.-H. Wong; D.L. Barnard; D.F. Smee (pp. 10-17).
Viramidine, the 3-carboxamidine derivative of ribavirin, was effective against a spectrum of influenza A (H1N1, H3N2 and H5N1) and B viruses in vitro, with the 50% effective concentration (EC50) ranging from 2 to 32μg/ml. The mean 50% cytotoxic concentration (CC50) in the MDCK cells used in these experiments was 760μg/ml. Ribavirin, run in parallel, had a similar antiviral spectrum, with EC50 values ranging from 0.6 to 5.5μg/ml; the mean CC50 for ribavirin was 560μg/ml. Oral gavage administrations of viramidine or ribavirin to mice infected with influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), B/Hong Kong/5/72 or B/Sichuan/379/99 viruses were highly effective in preventing death, lessening decline in arterial oxygen saturation, inhibition of lung consolidation and reducing lung virus titers. The minimum effective dose of viramidine in these studies ranged from 15 to 31mg/kg/day, depending upon the virus infection, when administered twice daily for 5 days beginning 4h pre-virus exposure. The LD50 of the compound was 610mg/kg/day. Ribavirin's minimum effective dose varied between 18 and 37.5mg/kg/day with the LD50 determined to be 220mg/kg/day. Viramidine's efficacy was also seen against an influenza A/NWS/33 (H1N1) virus infection in mice, when the compound was administered in the drinking water, the minimum effective dose being 100mg/kg/day. Delay of the initiation of either viramidine or ribavirin therapy, using the approximate 1/3 LD50 dose of each, was protective as late as 48h after exposure to the A/NWS/33 virus. While both compounds appear to have similar efficacy against influenza virus infections, when one considers the lesser toxicity, viramidine may warrant further evaluation as a possible therapy for influenza.
Keywords: Viramidine; Ribavirin; Influenza
Antiviral efficacy of VP14637 against respiratory syncytial virus in vitro and in cotton rats following delivery by small droplet aerosol by Philip R. Wyde; Sylvie Laquerre; Srikrishna N. Chetty; Brian E. Gilbert; Theodore J. Nitz; Daniel C. Pevear (pp. 18-26).
VP14637, the lead compound in a series of substituted bis-tetrazole-benzhydrylphenols developed by ViroPharma Incorporated, was evaluated for antiviral efficacy against respiratory syncytial virus (RSV) in vitro in cell culture and in vivo in cotton rats. A selective index of>3000 (≥2000 times greater than that observed for ribavirin) was determined in the in vitro studies for this compound against both RSV A and B subtypes. In cotton rats, animals given as little as 126μg drug/kg by small droplet aerosol in divided doses starting 1 day after experimental virus infection with either a RSV A or B subtype consistently had significantly lower mean pulmonary RSV titers and reduced histopathological findings than mock-treated animals or cotton rats given placebo (vehicle-treated animals). No cotton rat treated with aerosols of VP14637 during these studies manifested any evident untoward responses. Thus, VP14637 exhibited good selective antiviral efficacy both in vitro and in vivo.
Keywords: RSV; Antiviral; Cotton rats; Respiratory syncytial virus; VP14637; Aerosol delivery
Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir by Louise Doyon; Sonia Tremblay; Lise Bourgon; Elizabeth Wardrop; Michael G. Cordingley (pp. 27-35).
Tipranavir is a novel, non-peptidic protease inhibitor, which possesses broad antiviral activity against multiple protease inhibitor-resistant HIV-1. Resistance to this inhibitor however has not yet been well described. HIV was passaged for 9 months in culture in the presence of tipranavir to select HIV with a drug-resistant phenotype. Characterization of the selected variants revealed that the first mutations to be selected were L33F and I84V in the viral protease, mutations which together conferred less than two-fold resistance to tipranavir. At the end of the selection experiments, viruses harbouring 10 mutations in the protease (L10F, I13V, V32I, L33F, M36I, K45I, I54V, A71V, V82L, I84V) as well as a mutation in the CA/SP1 gag cleavage site were selected and showed 87-fold decreased susceptibility to tipranavir. In vitro, tipranavir-resistant viruses had a reduced replicative capacity which could not be improved by the introduction of the CA/SP1 cleavage site mutation. Tipranavir resistant viruses showed cross-resistance to other currently approved protease inhibitors with the exception of saquinavir. These results demonstrate that the tipranavir resistance phenotype is associated with complex genotypic changes in the protease. Resistance necessitates the sequential accumulation of multiple mutations.
Keywords: Tipranavir; HIV; Resistance
Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds by Cheng-Wen Lin; Fuu-Jen Tsai; Chang-Hai Tsai; Chien-Chen Lai; Lei Wan; Tin-Yun Ho; Chang-Chi Hsieh; Pei-Dawn Lee Chao (pp. 36-42).
The 3C-like protease (3CLpro) of SARS-coronavirus mediates the proteolytic processing of replicase polypeptides 1a and 1ab into functional proteins, becoming an important target for the drug development. In this study, Isatis indigotica root extract, five major compounds of I. indigotica root, and seven plant-derived phenolic compounds were tested for anti-SARS-CoV 3CLpro effects using cell-free and cell-based cleavage assays. Cleavage assays with the 3CLpro demonstrated that IC50 values were in micromolar ranges for I. indigotica root extract, indigo, sinigrin, aloe emodin and hesperetin. Sinigrin (IC50: 217μM) was more efficient in blocking the cleavage processing of the 3CLpro than indigo (IC50: 752μM) and beta-sitosterol (IC50: 1210μM) in the cell-based assay. Only two phenolic compounds aloe emodin and hesperetin dose-dependently inhibited cleavage activity of the 3CLpro, in which the IC50 was 366μM for aloe emodin and 8.3μM for hesperetin in the cell-based assay.
Keywords: SARS-coronavirus; 3C-like protease; Isatis indigotica; root; Phenolic compounds
Sensitivity of influenza viruses to zanamivir and oseltamivir: A study performed on viruses circulating in France prior to the introduction of neuraminidase inhibitors in clinical practice by O. Ferraris; N. Kessler; B. Lina (pp. 43-48).
Influenza virus neuraminidase inhibitors (NAIs) were introduced in clinical practice in various parts of the world since 1999 but were only scarcely distributed in France. Prior to the generalization of zanamivir and oseltamivir utilization in our country, we decided to test a large panel of influenza strains to establish the baseline sensitivity of these viruses to anti-neuraminidase drugs, based upon a fluorometric neuraminidase enzymatic test. Our study was performed on clinical samples collected by practitioners of the GROG network (Groupe Régional d’Observation de la Grippe) in the south of France during the 2002–2003 influenza season. Out of 355 isolates tested in the fluorometric neuraminidase activity assay, 267 isolates could be included in inhibition assay against anti-neuraminidase drugs. Differences in IC50 range were found according to the subtype and the anti-neuraminidase drug. Influenza B and A/H1N1 viruses appeared to be more sensitive to zanamivir than to oseltamivir (mean B IC50 values: 4.19nM versus 13nM; mean H1N1 IC50 values: 0.92nM versus 1.34nM), while A/H1N2 and A/H3N2 viruses were more sensitive to oseltamivir than to zanamivir (mean H3N2 IC50 values: 0.67nM versus 2.28nM; mean H1N2 IC50 values: 0.9nM versus 3.09nM). Out of 128 N2 carrying isolates, 10 isolates had zanamivir or oseltamivir IC50 values in upper limits compared to their respective data range. Sequencing of the neuraminidase of these outliers N2 highlighted several mutations, but none of them were associated with resistance to neuraminidase inhibitors.
Keywords: Influenza; Neuraminidase inhibitors; Resistance