Synergistic Inhibition of Enterovirus 71 Replication by Interferon and Rupintrivir

Methods. Through a bioinformatics analysis, several cellular proteins in the IFN response pathway were identified as susceptible substrates that might be degraded by the EV71-encoded 3C protease (3C(pro)). Results. Indeed, IRF9 was shown to be vulnerable to 3C(pro) cleavage, as revealed by enzyme-based and cell-based assays. Thus, the IFN-mediated antiviral mechanism compromised by the viral 3C(pro) in EV71-infected cells may be accountable, at least partially, for that IFN-alpha cannot inhibit EV71 replication. Because rupintrivir (AG7088) is known to be an effective EV71 inhibitor, we investigated the effects of the combination of rupintrivir and IFN-alpha on EV71 replication and found that they strongly synergized with each other in inhibiting EV71 replication. Conclusions. Because rupintrivir was shown to be generally tolerable in earlier clinical investigations, it is worth evaluating whether a combination of rupintrivir and IFN-alpha could be an effective treatment for EV71.