Antiviral Mechanisms of Pyridyl Imidazolidinones and Pyrazolo[3,4-d]Pyrimidines, Two Novel and Potent Inhibitors for Enteroviruses

Enterovirus infections occurred frequently in Taiwan. The associated diseases with severe complications continuously pose unbearable threat to young children. The absence of effective vaccines for most enterovirus infections highlights an urgent necessity for development of effective antiviral drugs. Recently two novel and potent enterovirus inhibitors, pyridyl imidazolidinones (“Z” class compounds) and pyrazolo[3,4-d]pyrimidines (“M”class compounds) have been discovered by our team. This proposal aims to study the detailed antiviral mechanism for these two compounds. Genetic approach will be used to identify the molecular target in EV71 for “Z” and “M” compounds. Sequence analysis of the plaque purified resistant viruses and mutagenesis in the infectious EV71 clones (maker rescue strategy) will be conducted to identify the viral genes the compound is targeting to. Biochemical approach will be used to comprehend the effect of “M” compound on viral protease. Inhibitory effect of “M” compound on viral protease activity in cell free system and in EV71-infected cells will be performed. The effects of “M” compound on RNA binding activity of EV71 protease and the influence of viral protease-induced cellular responses will be also evaluated. Another goal of this proposal is to functionally study the cellular proteins interacting with viral IRES, a promising target for anti-picornavirus drug discovery. Proteomic approach has been used to identify several novel cellular proteins associated with EV71 IRES in the previous study. This proposal will evaluate the effects of these cellular proteins on viral protein translation in vitro and in vivo. It is our belief that the results obtained from this proposal will not only help to elucidate the relationship between viral targets and potential drug leads, but also to dissect how drugs can interrupt the viral-host interactions.

Project ID:PA9405-0119
External Project ID:NSC94-3112-B182-006