In vitro discovery of a therapeutic lead for HFMD from a library screen of rocaglates/aglains

The lack of an effective antiviral treatment for enteroviruses, including the human enterovirus A71 (EV-A71), has resulted in an immense global healthcare burden associated with hand-foot-and-mouth disease (HFMD). Rocaglates and aglains belong to a family of compounds produced by Aglaia genus plants. Since the initial discovery of rocaglates in 1982, various rocaglates and aglains have been synthesized and extensively studied as anticancer and antiviral agents. Here, we report our studies towards the discovery of a novel aglain derivative as an EV-A71 inhibitor and work to decipher its antiviral effect. From an immunofluorescence-based phenotypic screen of a library of 296 rocaglate and aglain derivatives, we identified a lead aglain derivative which effectively suppressed EV-A71 replication by 2.3 log fold at a non-cytotoxic concentration. Further validation revealed inhibition of EV-A71 across multiple cell types and a pan-enterovirus inhibitory spectrum against other enteroviruses. Subsequent mechanistic investigation revealed interference with EV-A71 intracellular post-entry events including viral RNA transcription and translation. Findings from this study have established a strong foundation for development of aglain scaffolds as much needed antiviral agents for HFMD, paving the way for future medicinal chemistry optimization and in vivo studies.