Journal
JOURNAL OF MEDICAL VIROLOGY
Volume 94, Issue 11, Pages 5415-5424Publisher
WILEY
DOI: 10.1002/jmv.27975
Keywords
EV-A71; host factor; intestinal organoids; kinase inhibitors; Rock1
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Funding
- Shanghai Rising-Star Program [22QA1408800]
- Health and Medical Research Fund (HMRF), commissioned programme for control of infectious diseases CID-HKU1-3 of the Food and Health Bureau of the HKSAR government [17161272, 19180392]
- Research Grants Council [C7042-21G, 17105420]
- Health@InnoHK, Innovation and Technology Commission, of HKSAR government
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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.
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.
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