ro-09-0410 and viroxime

Topics: Benzimidazoles; Chalcone; Chalcones; Common Cold; Flavonoids; Humans; Interferon Type I; Oximes; Rhinovirus; Sulfonamides

DCF (dichloroflavan), enviroxime, chalcone Ro-09-0410 and HuIFN (Human interferon)-alpha 2, HuIFN-beta, HuIFN-beta X 401 and HuIFN-gamma, showed antiviral activity in vitro against RV2 (rhinovirus type 2) and RV9. Binary combinations of these drugs showed synergistic activity of which the combinations of HuIFN-gamma or HuIFN-alpha and enviroxime were of most interest. They were studied in more detail in tissue culture by virus yield experiments and in organ culture of human embryonic nasal epithelium and human embryonic tracheal culture in which there was a potent antiviral synergy. These results indicate that such combinations of drugs may be worthy of clinical study.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Chalcone; Chalcones; Cytopathogenic Effect, Viral; Drug Synergism; Flavonoids; Humans; Interferon Type I; Interferon-gamma; Oximes; Rhinovirus; Semliki forest virus; Sulfonamides

The modes of action of antirhinovirus agents and mechanisms of resistance to the agents are compared. Chalcone Ro 09-0410, 4',6-dichloroflavan (DCF) and RMI-15,731, which were active against rhinoviruses, inactivated the virus directly. Inactivation was associated with the binding of the agents to the virus particles, since the infectivity, reduced by exposure to the compounds, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]chalcone to rhinovirus type 2 was inhibited by any of the three unlabelled agents. Furthermore, virus sublines selected for resistance to both dichloroflavan and RMI-15,731 showed cross-resistance to chalcone and vice versa. These findings indicate that the three agents exert their activities through the same mode of action (namely binding to or interaction with a specific site on the viral capsid protein) and that the binding or interaction sites for these three agents are either the same or very close to each other. Since the sublines resistant to chalcone and to RMI-15,731 have little or no capability to bind to chalcone, the resistance to these agents is conferred by changes in the viral capsid protein. On the other hand, flavone Ro 09-0179 and enviroxime, which were active widely against picornaviruses, had no ability to inactivate the virus directly, and their antiviral activity was not associated with the capsid protein.

Topics: Benzimidazoles; Capsid; Chalcone; Chalcones; Drug Resistance, Microbial; Flavonoids; Furans; Oximes; Quercetin; Rhinovirus; Sulfonamides

Modes of action of five antirhinovirus agents were compared. Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 were active preferentially against human rhinovirus. Serotypes of the virus varied in their susceptibility to these three agents, whereas Ro 09-0179 and enviroxime showed activity against all the serotypes of the virus tested to date. Ro 09-0410, RMI-15,731, and 4',6-dichloroflavan inactivated the virus directly, although 4',6-dichloroflavan did so only slightly. Inactivation by 4',6-dichloroflavan and RMI-15,731 was associated with the binding of the agents to the virus, since the infectivity, reduced by exposure to the agents, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]Ro 09-0410 to human rhinovirus type 2 was inhibited by unlabeled Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 but not by Ro 09-0179 or enviroxime. Furthermore, subtypes resistant to both 4',6-dichloroflavan and RMI-15,731 showed cross-resistance to Ro 09-0410 and vice versa. On the other hand, sublines resistant to these three agents were not cross-resistant to Ro 09-0179 or enviroxime. These results indicate (i) that Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 exert their activities through the same mode of action, namely, binding to or interaction with some specific site on the viral capsid protein, and (ii) that the binding or interaction sites for these three agents are either the same or very close to each other.

Topics: Antiviral Agents; Benzimidazoles; Binding, Competitive; Cells, Cultured; Centrifugation, Density Gradient; Chalcone; Chalcones; Chloroform; Cytopathogenic Effect, Viral; Drug Resistance, Microbial; Flavonoids; Furans; Humans; Oximes; Quercetin; Rhinovirus; Sulfonamides