The Mpro Structure-Based Modifications of Ebselen Derivatives for Improved Antiviral Activity Against SARS-CoV-2 Virus

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