ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed millions of lives and caused innumerable economic losses worldwide. Unfortunately, state-of-the-art treatments still lag behind the continual emergence of new variants. Key to resolving this issue is developing antivirals to deactivate coronaviruses regardless of their structural evolution. Here, we report an innovative antiviral strategy involving extracellular disintegration of viral proteins with hyperanion-grafted enediyne (EDY) molecules. The core EDY generates reactive radical species and causes significant damage to the spike protein of coronavirus, while the hyperanion groups ensure negligible cytotoxicity of the molecules. The EDYs exhibit antiviral activity down to nanomolar concentrations, and the selectivity index of up to 20,000 against four kinds of human coronavirus, including the SARS-CoV-2 Omicron variant, suggesting the high potential of this new strategy in combating the COVID-19 pandemic and a future "disease X."