Substituted homo-isoflavonoids were synthesized in order to study their in vitro anti-picornavirus activity. The maximum non-toxic concentration of the compounds for susceptible cells (Hela) was determined, and the ability of non-cytotoxic concentrations to interfere with plaque formation by human rhinovirus (HRV) 1Band 14 and poliovirus (PV) 2 was examined. All the tested compounds were weakly effective against PV-2, while they exhibited a variable degree of activity against HRV-1 Band-14 infection. Serotype 1B was much more sensitive than 14 to the action of the compounds, and the presence of one or more chlorine atoms increased the antiviral effect in all homoisoflavonoids tested, confirming the positive influence of this substituent on activity.
Members of the family Picornaviridae, which comprise rhinoviruses and enteroviruses, are responsible for several human diseases. It is estimated that over 100 serotypes of human rhinoviruses (HRV) cause approximately half of all cases of the common cold. Also, poliomyelitis still represents a relevant health problem in some countries of the world, despite a dramatic decrease in its incidence as a result of intensive vaccination programmes in developed countries. There therefore exists a need to search for effective chemotherapeutic agents for picornavirus infections.Several classes of flavonoids, isolated from plants utilized in traditional medicine, possess a well recognized anti-picornavirus activity (Van Hoof et al.,1984;Kaul et al., 1985;Tsuchiya et al., 1985). Among polyhydroxylated flavones, quercetin was originally described to reduce the infectivity and the intracellular replication of poliovirus type 1 (PV-1), but not of PV-2 or PV-3. Hesperetin, a flavanone, was able to interfere with PV-1 infection of cell monolayers without affecting virus infectivity (Kaul et al., 1985). 3-Methoxylated flavones, such as chrysosplenol B and C, and axillarin, were found to have potent anti-HRV activity, whereas flavones without a methoxyl group at the 3-position had no anti-rhinovirus activity (Tsuchiya et al., 1985). Beside an effect on HRVs, 4′,5-dihydroxy-3,3′,7-trimethoxyflavone (Ro-09-0179) also exerted an inhibitory activity against coxsackieviruses in tissue cultures (Kaul et al., 1985). The mechanism of action of flavonoids has been attributed to interference with an early stage of viral infection, probably represented by viral RNA synthesis (Castrillo et al., 1986;Gonzales et al., 1990).The study of various synthetic flavones, structurally related to natural flavonoids, confirmed the anti-picornavirus activity of this class of compounds (De Meyer et al., 1991;Desideri et al., 1995). Among the derivatives studied by us, flavanones were generally less effective against picornaviruses than flavones, and 3-hydroxy or 3-methoxyflavones were more active than 3-unsubstituted flavones. The presence of a 3-hydroxy group increased the anti-PV potency, whereas a 3-methoxy group enhanced the effect against HRV-1B ( Desideri et al., 1995). In order to further study the influence on anti-picornavirus activity of the substituent in position 3 of synthetic flavones, we extended our research to esters of chloroflavon-3-ols with natural occurring hydroxybenzoic and hydroxycinnamic acids, i.e. gallic, syringic, caffeic, vanillic and ferulic acids (compounds 2 a-h, 3 a-l). Materials and Methods: VirologyCells HeLa (Ohio) cells were routinely grown at 37°C in 75 cm 2 tissue culture flasks using Eagle's MEM supplemented with 100 µg/ml of streptomycin and 100 U/ml of penicillin G. Eight percent heat-inactivated fetal calf serum (FCS) was added for cell growth (growth medium); the concentration was reduced to 2% for cell maintenance (maintenance medium). The in vitro antiviral activity against picornaviruses (rhinovirus serotype 1B ...
A microassay was developed to detect human herpesvirus 6 (HHV-6) binding to its cellular receptor using flow cytometry. Comparable results were obtained either by using HHV-6 preparations conjugated with fluorescein isothiocyanate or by indirect immunofluorescent labeling of membrane-bound virus using as primary antibody a monoclonal antibody specific for the HHV-6 gp60/110 envelope glycoprotein. Virus attachment to the plasma membrane was specific and saturable. As expected, among cell lines of various origin, maximum binding was detected on human T-lymphoid cells (HSB-2). Papain digestion of HSB-2 cells prevented HHV-6 attachment and reduced significantly virus infection, indicating the involvement of a protein-based receptor in the attachment step. After removal of the protease, virus receptors were resynthesized and their regeneration was prevented partially by cycloheximide, an inhibitor of protein synthesis. Unexpectedly, only high concentrations (mg/ml) of soluble heparan sulfate and heparin inhibited HHV-6 binding and infection. Under the same conditions, few micrograms (per ml) of heparin suppressed completely herpes simplex type 1 (HSV-1) attachment to the same cell line. Treatment of HSB-2 cells with heparitinase and heparinase, at doses that reduced significantly HSV-1 attachment, had little effect on HHV-6 binding to the cell membrane, indicating a different requirement of heparan sulfate-containing glycosaminoglycans for the two herpesviruses. These data suggest that protein components of the cellular membrane play an essential role in HHV-6 binding and infection while heparan sulfate-glycos-aminoglycans appear to be involved only partially in virus-receptor interaction.
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