In vitro Antimyxovirus and Anti-Human Immunodeficiency Virus Activities of Polyoxometalates

Abstract

Polyoxometalates have been shown to inhibit the replication of retro-, toga-, paramyxo- and herpesviruses. The primary mechanism of the anti-human immunodeficiency virus type 1 (HIV-1) action of polyoxometalates seems to be inhibition of binding of virus to cells and inhibition of syncytium formation. Since myxoviruses and HIV-1 are known to interact with the cytoplasmic membrane by adsorption and penetration of virus and by fusion of infected and uninfected cells, 25 polyoxometalates were examined for anti-ortho-, anti-paramyxovirus and anti-HIV-1 activity in vitro. Of the 25 compounds evaluated, 24 showed antiviral effects against influenza virus A, 11 showed activity against respiratory syncytial virus, six showed activity against measles virus, and 23 were considered effective against HIV-1 at a lower concentration than that producing cytotoxicity. Four polyoxotungstates which had potent inhibitory effects were examined for inhibitory effects against additional ortho- and paramyxoviruses, and proved to have a broad spectrum of antimyxoviral activity. HS-058, the Keggin sandwich compound K10Fe4(H2O)2(PW9O34)2·nH2O, was inhibitory against influenza viruses A and B, respiratory syncytial virus, measles virus, and parainfluenza virus 2, with median effective concentrations of 1.4, 21.8, 7.4, 0.8 and 0.32 μ,M, respectively. However, HS-058 had no effect on parainfluenza virus 3 or mumps virus. The median cytotoxic concentration of HS-058 for Madin-Darby canine kidney (MDCK) and HEp-2 cells was more than 200 μM and that for HMV-2 and Vero cells was about 50 μM. When HS-058 was added at different times after influenza A and respiratory syncytial virus infection, it inhibited binding of the latter but not of the former to cells. However, at higher concentrations, HS-054 and HS-058 inhibited haemolysis of chick erythrocytes by influenza virus and syncytium formation involving respiratory syncytial virus-infected cells and uninfected cells. Four times the median effective antiviral concentration of HS-058 completely inhibited the growth of influenza virus A in MDCK cells when compound was added before virus adsorption. Furthermore, when HS-058 was added after virus adsorption, it inhibited the yield of virus in MDCK cells infected at low but not at high multiplicity of infection.

Influenza Virus-Inhibitory Effects of a Series of Germanium- and Silicon-Centred Polyoxometalates

“…The EC so values determined in the present study, albeit with different strains of virus, were significantly higher with this series of POM than with those reported by Shigeta et al (1995). Ikeda et a!.…”

“…Such data suggest these materials to be more selective than expected. Studies using HIV-1 have shown that these large and negatively charged molecules are active at the cell surface (Inouye et al, 1993;Judd et al, 1994), although certain smaller-sized POM have been shown to readily penetrate cell membranes (Hill et al, 1995). The latter observation suggests possible intracellular roles for the antiviral activity of these materials.…”

“…Four of these compounds had the double Keggin and one an alpha Keggin structure shown in a previous publication (Hill et al, 1995). Compounds JM-2919, JM-2922 andJM-2923 were synthesized according to published procedures.…”

“…Herpesviruses have been reported to be inhibited by some of these compounds both in vitro (Fukuma et al, 1991;Yamamoto et al, 1992;Ikeda et al, 1993) and in vivo (Ikeda et al, 1994). Other viruses inhibited include toga-, rhabdo-, arena-, paramyxo-and murine retroviruses (Yamamoto et al, 1992;Ikeda et al, 1993;Shigeta et al, 1995). Ofparticular pertinence to the present study has been the reported activity of POM against influenza A and B viruses (Ikeda et al, 1993;Shigeta et al, 1995), the inhibitory materials being polyoxotungstates with the 'Keggin' or 'Keggin sandwich' structure, with a number of these materials containing silicon.…”

“…Several studies have indicated that certain paM are significantly inhibitory to human immunodeficiency virus (HIV) in vitro (Hill et al, 1990(Hill et al, , 1993Yamamoto et al, 1992;Inouye et al, 1993;Blasecki, 1994;Judd et al, 1994;Kim et al, 1994;Swart & Meijer, 1994;Moore etal., 1995;Shigeta et al, 1995). Herpesviruses have been reported to be inhibited by some of these compounds both in vitro (Fukuma et al, 1991;Yamamoto et al, 1992;Ikeda et al, 1993) and in vivo (Ikeda et al, 1994).…”