Antipoliovirus activity and mechanism of action of 3-methylthio-5-phenyl-4-isothiazolecarbonitrile.

ABSTRACT

Our previous studies described the synthesis and the antiviral activity of 3,4,5-trisubstituted isothiazole derivatives that were found to be particularly effective against enteroviruses. Compound 3-methylthio-5-phenyl-4-isothiazolecarbonitrile (IS-2) exhibited an interesting anti-poliovirus activity with a high selectivity index. In the present study we investigated the mechanism of action of this compound. Studies on the time of IS-2 addition to poliovirus type 1 infected cells suggested that the compound may inhibit some early process of viral replication. In order to determine its mechanism of action, we evaluated the rate of attachment and internalization of purified [³H]uridine-labeled poliovirus to HEp-2 cells in the presence or absence of IS-2. No effect on poliovirus adsorption and internalization to host cells was detected. We also investigated the influence of the compound on virus uncoating using labeled poliovirus and measuring the radioactivity of oligoribonucleotides formed from viral RNA susceptible to ribonuclease. These experiments demonstrated that poliovirus uncoating is influenced by IS-2 action.