Arsenic trioxide could promote SARS-CoV-2 NSP12 protein degradation.

The global dissemination and infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become a worldwide crisis with staggering confirmed cases and death tolls. Although prophylactic vaccines are widely applied to curb the spread of the virus, these protections are greatly weakened by the emergence of SARS-CoV-2 variants. Non-structural protein 12 (NSP12) of SARS-CoV-2 is an RNA-dependent RNA polymerase that plays an essential role in viral replication and transcription, representing a promising target for drug development. Currently, extensive drugs are designed to specifically target and inhibit NSP12 activity, while highly infectious and drug-resistant variants have significantly compromised their efficacy. Here, we identified that arsenic trioxide (ATO) could specifically reduce not only WT SARS-CoV-2 NSP12 but also mutant NSP12 levels, along with low toxicity. Moreover, the reduction of NSP12 was caused by its robust ubiquitination and subsequent degradation via the ubiquitin-proteasome pathway after ATO treatment. Of note, STIP1 homology and U-box containing protein 1 was found to be the E3 ligase responsible for the ubiquitination and degradation of NSP12 by ATO. In short, our findings provide a potential intervention to restrict virus replication and may broaden the scope of therapeutic application for ATO.