Abstract
Human Enterovirus 71 (EV71), one of the major etiological agents of the hand, foot, and mouth disease (HFMD), represents a serious global health threat against which there is no FDA‐approved treatment. Enteroviruses utilize a highly structured RNA domain, known as a type I Internal Ribosome Entry Site (IRES), to facilitate cap‐independent translation and genome replication by recruiting multiple host RNA‐binding proteins (ITAFs) that fine‐tune translation. Of particular interest, the stem‐loop II (SLII) IRES domain has been shown to specifically interact with several ITAFs such as hnRNP A1 and AUF1, having the SLII‐bulge as the binding surface to effectively modulate viral translation. Further studies showed that deletions and mutations to the bulge motif inhibit EV71 replication by offsetting IRES‐driven translation. Altogether, the results provide strong basis to classify the EV71 SLII domain as a promising target to develop novel antiviral agents. Here, we screened an RNA focused small molecule (rfsm) library against the EV71 SLII domain which yielded in the identification of six rfms that specifically bind to the bulge motif when detected by NMR spectroscopy and titration calorimetry. One of the aforementioned rfms impairs IRES‐dependent translation and displays dose‐dependent antiviral properties in cell culture. Furthermore, the NMR‐derived 3D structure of the SLII‐rfsm complex provides evidence that the small molecule binds to the bulge to induce a conformational change that exposes key nucleotides on the binding site for AUF1. This was further validated both in an in vitro biochemical assay and in vivo. Collectively, these results suggest an allosteric mechanism of inhibition in which the rfsm stabilizes the SLII‐AUF1 complex to repress translation. Therefore, this study provides structural and functional insight to develop novel RNA‐focused small molecule inhibitors of the Enterovirus genus.Support or Funding InformationNIH R01GM126833
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