Targeting WDPF domain of Hsp27 achieves a broad spectrum of antiviral

Enterovirus A71 (EV-A71) is a positive-sense single-stranded RNA virus, which hijacks host proteins to benefit viral internal ribosome entry site (IRES)-dependent protein translation and further propagation. We demonstrated that serine 78 (S78) phosphorylation of Hsp27 is critical for Hsp27/hnRNP A1 relocalization upon EV-A71 infection. Here, we report that the deletion of WDPF and ACD domains disturbs subcellular localization of Hsp27, resulting in partial nuclear translocation. The domain deletion-induced Hsp27 nuclear translocation fails to direct hnRNP A1 translocation. The 2A^pro-induced IRES activity and viral replication are suppressed by the deletion of WDPF or ACD domain. Surprisingly, a peptide (WDPF) dramatically inhibits S78 phosphorylation. Therefore, hnRNP A1 translocation, viral IRES activity, and viral protein translation and propagation are all strongly suppressed by the WDPF peptide, but not by peptide without WDPFR sequence (ΔWDPF). Moreover, the WDPF peptide also has potent antiviral activity on other RNA virus (e.g., coronavirus HCoV-OC43) and DNA virus (e.g., HSV-1 and HBV). Peptide treatment with kinase inhibitor Sorafenib brings an additional inhibitory effect on HCoV-OC43 and HSV-1. Taken together, we uncover a crucial role of WDPF domain in S78 phosphorylation for EV-A71-induced hnRNP A1 nuclear translocation, IRES-dependent viral protein translation, and EV-A71 propagation. Our results explore a new path for target-based pan-antiviral strategy.