Molecular basis of drug resistance to new antirhinovirus agents

Abstract

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.

Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization

“…Cross resistance was observed between dichloroflavan, chalcone, RMI 15,731 and MDL20,610 for HRV2 [11,14], and between SDS, arildone, dichloroflavan, and chalcone for HRV 1 B [25]. On the other hand, mutants of HRV 9 selected by chalcone were not cross resistant to dichloroflavan [1].…”

Picornavirus inhibitors

“…Of 53 rhinovirus serotypes tested, 46 were inhibited by Ro 09-0410 (Ishitsuka et al, 1982a). Mutant rhinoviruses resistant to chalcone were cross-resistant to BW683C or RMI-15,731 (Ishitsuka et al, 1986). These results indicate that the three compounds had a similar mode of action based on their binding to virion particles.…”

“…11) is an active compound against rhinoviruses and binds to the viral capsid (Ishitsuka et al, 1982a, b;Ninomiya et al, 1984, 1985,1990). Radioactive chalcone (Ro 09-0410) binds specifically to rhinovirus particles and this binding is inhibited by BW683C or RMI-15,731 (Ninomiya et al, 1985;Ishitsuka et al, 1986). Of 53 rhinovirus serotypes tested, 46 were inhibited by Ro 09-0410 (Ishitsuka et al, 1982a).…”

A comprehensive review on the antiviral activities of chalcones

“…The goal of identifying anti-rhinovirus agents was to develop compounds with higher therapeutic ratio to limit viral infectivity. Chalcone Ro 09-0410, 4 0 ,6-dichloroflavan (DCF) and RMI-15,731(1-[5-tetradecyloxy-2-furanyl]-ethanone), were suggested by several studies for directly inactivating the virus [62]. However, the binding site of the aforementioned compounds on the capsid was found to have slight conformational differences among viral serotypes [62].…”

“…Chalcone Ro 09-0410, 4 0 ,6-dichloroflavan (DCF) and RMI-15,731(1-[5-tetradecyloxy-2-furanyl]-ethanone), were suggested by several studies for directly inactivating the virus [62]. However, the binding site of the aforementioned compounds on the capsid was found to have slight conformational differences among viral serotypes [62]. A minor change in the binding site was proposed since chalcones can bind to the DCF resistant rhino virus type, and no cross-resistance was seen between RMI and DCF [62].…”