HR2-Based Derivative Peptides of Spike Protein Confer Inhibitory Efficacy against Porcine Deltacoronavirus.

Porcine deltacoronavirus (PDCoV) causes severe diarrhea in piglets and poses a potential public health risk due to cross-species transmission. Antiviral drugs are urgently needed. We designed peptides HR1P and HR2P from the viral spike (S) protein and evaluated their antiviral efficacy. HR2P exhibited potent in vitro activity (EC50 = 6.65 μM), maintained efficacy against HR1-mutated variants, and showed broad cross-species inhibitory activity across avian, nonhuman primate, and human-derived cells. Molecular docking analysis predicted that HR2P targets conserved structural sites shared with PEDV and TGEV, avoiding observed HR1 mutation sites. In piglets, early-stage HR2P intervention effectively reduced viral loads in the jejunum and ileum, alleviating clinical diarrhea. In addition, pharmacokinetic (PK) analysis further confirmed that intramuscular (IM) administration of HR2P (10 mg/kg) achieved stable systemic exposure, with a peak plasma concentration (Cmax = 194.6 μg/mL) substantially exceeding the in vitro EC50. These findings suggest HR2P as a potential broad-spectrum therapeutic candidate.