On the mechanism of selective inhibition of enterovirus multiplication by 2-(α-hydroxybenzyl)-benzimidazole

Abstract

The mechanism of action of 2-(α-hydroxybenzyl)-benzimidazole (HBB), a selective inhibitor of enterovirus multiplication, was investigated. At a concentration of 219 μ M or 49 μg/ml, HBB had no effect on adsorption or penetration of ECHO 12 virus, but inhibited a process which commenced during the second half of the latent period and continued into the second half of the exponential increase phase of virus reproduction. Given during the exponential increase in virus, HBB caused complete cessation of further virus production within 30–45 minutes of its addition. A possible biochemical basis for these findings was provided by the demonstration that HBB inhibits the synthesis of infective viral RNA of ECHO 12 virus and that the bulk of infective RNA of this virus is synthesized during the exponential increase in virus. HBB also inhibited the synthesis of infective viral RNA of Coxsackie A9 and Coxsackie B4 viruses. With these viruses the dose-effect curves describing inhibition of viral RNA synthesis followed closely those depicting inhibition of complete virus. In ECHO 12 virus-infected cells, however, a substantial amount of infective viral RNA was synthesized in the presence of 65 μ M HBB, although no increase in infective virus was observed. HBB had no direct irreversible inactivating effect on the infectivity of viral RNA, nor did it interfere with its uptake by cells. In HBB-treated cells, in which replication of infective viral RNA was inhibited, production of complement-fixing antigen was also inhibited. Concentrations of HBB sufficient to inhibit production of infective viral RNA had no effect on host cell RNA synthesis as studied by uptake of radioactive precursors into RNA. Furthermore, the rate of host cell multiplication was unaffected by HBB.