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.