Ebsulfur and Ebselen as highly potent scaffolds for the development of potential SARS-CoV-2 antivirals

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (M pro ) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 M pro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC 50 ) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074–0.91 μM. Notably, the molecules containing furane substituent displayed higher inhibition against M pro , followed by Ebselen 1i (IC 50  = 0.074 μM) and Ebsulfur 2k (IC 50  = 0.11 μM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to M pro , while molecular docking suggested that 2k formed an S S bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of M pro to combat COVID-19.