Anthracyclines inhibit SARS-CoV-2 infection

ABSTRACT Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 μM, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors. IMPORTANCE Microbial metabolites are a rich source of bioactive molecules. The best examples are antibiotics and immunosuppressants that have transformed the practice of modern medicine and saved millions of lives. Recently, some microbial metabolites were reported to have antiviral activity, including the inhibition of Zika virus and Ebola virus. In this study, we discovered several microbial metabolites that effectively inhibit SARS-CoV-2 infection, including anthracyclines that have also been shown to inhibit other viruses including Ebola virus through enhancing interferon responses, which indicates potentially broad antiviral properties of these microbial metabolites and can lead to the discovery of pan-antiviral molecules.