In Vitro Discovery of a Therapeutic Lead for HFMD From a Library Screen of Rocaglates/Aglains

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ABSTRACT The lack of effective antiviral treatments for enteroviruses, including human enterovirus A71 (EV‐A71), have 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 mainly as anticancer agents. Here, we report the discovery of a novel aglain derivative as a potential EV‐A71 inhibitor. From an immunofluorescence‐based phenotypic screen of a library of 296 rocaglate and aglain derivatives, we identified a lead aglain which effectively suppressed EV‐A71 replication by 2.3 log fold at a non‐cytotoxic concentration, with a host cell CC50 of 21.78 µM, an EV‐A71 infection EC50 of 3.57 µM, and a selectivity index of 6.1. Further validation revealed inhibition of EV‐A71 across multiple human 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.

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