Rock1 is a novel host dependency factor of human enterovirus A71: Implication as a drug target

Human enterovirus A71 (EV-A71) is the major causative agent of hand-foot-and-mouth disease (HFMD) commonly associated with severe neurological diseases, particularly in children under 5 years of age. Several investigational therapeutic agents and vaccine candidates are being developed. However, no approved drug against EV-A71 infection is available, and no proven drug target has been identified. Since host kinases are key regulators of multiple signaling pathways in response to viral infections, here we screened a kinase inhibitor library and identified potent inhibitors against EV-A71 infection. Among the hits, GSK269962A, a Rho Associated Coiled-Coil Containing Protein Kinase (Rock) inhibitor with potent antiviral activity, was selected for further analysis. We found that this Rock inhibitor not only efficiently suppressed the replication of EV-A71 in RD cells, but also in human intestinal organoids, in a dose-dependent manner. Interestingly, small interfering RNA depletion of Rock1, but not Rock2, significantly restricted viral replication in RD cells, indicating that Rock1 is a novel host dependency factor for EV-A71 replication and can serve as a target for the development of anti-EV-A71 therapeutics.

Automated summary

In this study, potent inhibitors against EV-A71 infection were identified through screening a kinase inhibitor library. Among the hits, the Rock inhibitor GSK269962A was found to efficiently suppress EV-A71 replication in RD cells and human intestinal organoids in a dose-dependent manner. Knockdown of Rock1, but not Rock2, significantly restricted viral replication in RD cells, suggesting that Rock1 could serve as a novel host dependency factor and target for the development of anti-EV-A71 therapeutics.