Chimeric enediynes as potent antivirals against coronaviruses by targeting the conserved free-fatty-acid binding site on the spike protein.

Conventional targeted protein degradation (TPD) strategies operate by hijacking intracellular proteolytic machinery, limiting their therapeutic scope. Here, we present protein-radical-oxidation targeting enediyne chimera (PROTEC), a TPD platform that can be located exclusively outside of host cells and degrades pathogen proteins via a radical-based oxidative mechanism. The maleimide-fused enediyne core undergoes cycloaromatization under physiological conditions to generate reactive radical species. Strategic incorporation of sulfate-based hydrophilicity-adjusting groups (HAGs) restricts PROTEC activity to the extracellular space, enhancing biosafety. Using a ligand (spc14) that targets the conserved free fatty acid binding pocket, we demonstrate that PROTECs effectively degrade the coronavirus spike protein and potently inhibit seasonal coronaviruses. Further optimization through a propargyl ester moiety and increased sulfation yielded PROTEC-d, a lead compound with a half-maximal inhibitory concentration of 0.22 µM and a selectivity index exceeding 3000. Our findings establish PROTEC as a safe and versatile strategy for the extracellular degradation of pathogen proteins, with promising potential for broad-spectrum antiviral applications.