Chimeric Enediynes as Potent Antivirals against Coronaviruses by Targeting the Conserved Free-Fatty-Acid Binding Site on the Spike Protein

Abstract

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 condition 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