Inhibition of the Particle-associated RNA-dependent RNA Polymerase Activity of Influenza Viruses by Chelating Agents

SUMMARY Approximately 0.05 mm concentrations of the chelating agents bathocuproine and bathophenanthroline disulphonic acid disodium salts, which form very stable complexes with ‘soft’ heavy-metal ions such as zinc, inhibited in vitro the RNA-dependent RNA polymerase activity associated with influenza B/LEE/40 and A/RI-5+ (H2N2) viruses in the presence of a large molar excess of Mn(II) and Mg(II). Certain heterocyclic thiosemicarbazones also inhibited influenza RNA polymerase activity, although complete inhibition was not detected even with high concentrations (0.1 mm) of the compounds. Analogues of the active heterocyclic thiosemicarbazones, such as isatin 3-semicarbazone, which have reduced chelating activities for zinc, also had reduced inhibitory effects on influenza virus associated RNA polymerase activity. However, inhibition of influenza RNA polymerase activity by 0.1 mm-bathocuproine or 0.1 mm-isatin 3-thiosemicarbazone was not reversed by the addition of molar equivalent or excess concentrations of zinc. Relatively high concentrations of the chelating agents had no detectable effect on the haemagglutinin, neuraminidase or infectivity titres of influenza B/LEE/40 virus. The chelating agents may inhibit influenza virus-associated RNA polymerase activity by the formation of a ternary complex of enzyme-metal-ligand.