A comprehensive PDCoV-host proteome interaction map reveals potential antiviral targets.

Porcine deltacoronavirus (PDCoV), an enteric member of the coronavirus family, has emerged globally over the past decade, causing significant impacts on the swine industry. While studies of virus-host protein interactions provide crucial insights into viral engagement with host cells during infection, research specifically targeting PDCoV-host interaction factors remains limited. To identify host proteins involved in PDCoV replication, comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was employed to identify host proteins interacting with the PDCoV genomic RNA. Concurrently, affinity purification mass spectrometry (AP-MS) was utilized to identify host interactors of PDCoV-encoded proteins. A total of 671 host proteins were identified in our analysis. These host interactors participate in diverse cellular processes, including extensive representation of metabolic enzymes, transcription factors, RNA-binding proteins (RBPs), and intracellular signal transduction components. Construction of a comprehensive PDCoV-host protein interaction network map revealed that SYNCRIP (heterogeneous nuclear ribonucleoprotein Q, hnRNP Q), functions as a novel host restriction factor with PDCoV. SYNCRIP interacts with the N proteins of multiple coronaviruses and competitively displaces HUWE1 to bind the PDCoV N protein, thereby blocking its ubiquitin-proteasome-mediated degradation. Furthermore, Isoforsythiaside, a small-molecule inhibitor designed to target SYNCRIP, demonstrated substantial antiviral potential both in vitro and in vivo. In summary, this study provides a comprehensive catalog of functional PDCoV viral RNA (vRNA)/viral Protein (vProtein)-host protein interactions. This resource not only informs the understanding of pan-coronavirus infection mechanisms but also nominates host cellular processes as potential targets for antiviral intervention.