ABSTRACT
The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate, as an inhibitor of Mpro. Our docking of ebselen to crystal structure of Mpro catalytic pocket reveals a better fit of “tail-to-head” mode through noncovalent binding, suggesting modification of ebselen for its improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro and reducing steric hindrance. The inhibition of Mpro by ebselen derivatives (0.3 μM) was screened in both HPLC and FRET assays. Nine ebselen derivatives exhibited stronger inhibitory effect on Mpro with IC50 of 0.07 to 0.38 μM. Further evaluation of three derivatives showed the inhibition on SARS-CoV-2 viral replication with their IC50 values from 4.08 to 19.93 µM in HPAepiC cells, as compared to prototype ebselen at 24.61 μM. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.