Identification of Novel Amino Acid–based PROTACs Exhibiting Broad-Spectrum Antiviral Activity Against Enteroviruses

Enteroviruses threaten children's health, yet no antiviral drugs are available. We developed a series of AATacs by conjugating acylthiourea with basic or hydrophobic amino acids. Unlike PROTACs, AATacs hijack host endogenous E3 ligases to exert their function. The representative compound N-6 targets the EV-A71 3D polymerase for degradation via the ubiquitin-proteasome and autophagy-lysosomal pathways, thereby blocking viral replication. N-6 exhibits broad-spectrum activity against multiple enteroviruses with nanomolar to picomolar potency. In vivo, N-6 protected 60% of the infected mice from mortality, reduced tissue damage, and demonstrated a favorable safety profile, although further optimization for drug-likeness is required. This study establishes AATacs as a novel platform for targeted antiviral degraders and provides a promising candidate for anti-enterovirus drug development.