The Tetrahydroisoquinoline Derivative SP9 Exhibits Antiviral Activity Against PEDV and MHV

Coronaviruses exhibit high mutation rates and cross‐species transmissibility, posing a persistent threat to human and animal health and underscoring the urgent need for antivirals that can compensate for the limited crossprotection afforded by current vaccines. In this study, we synthesized a tetrahydroisoquinoline alkaloid (THIQA) derivative, 2‐[2‐(4‐chlorophenyl)ethyl]‐6,7‐dimethoxy‐1‐methyl‐1,2,3,4‐THIQ (SP9), and evaluated its antiviral activity against two phylogenetically distinct coronaviruses: porcine epidemic diarrhea virus (PEDV, α‐genus) and murine hepatitis virus (MHV, β‐genus). In vitro, SP9 dose‐dependently inhibited viral RNA synthesis, progeny virion production, and viral protein expression in both viruses. Time‐of‐addition analyses and dsRNA‐labeling assays localized the antiviral blockade at the replication stage. Mechanistically, SP9 disrupted autophagic flux by preventing autophagosome–lysosome fusion. In a lethal MHV‐challenge mouse model, SP9 significantly increased survival and accelerated bodyweight recovery. Together, these results identify SP9 as a novel coronavirus inhibitor that targets host autophagy, providing a promising lead for further optimization of tetrahydroisoquinoline (THIQ)‐based antivirals.