Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease

The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-M-pro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the treatment of coronavirus disease 2019 (COVID-19). In this study, a fragment-based strategy including potential antiviral quinazolinone moiety and glutamine- or glutamate-derived peptidomimetic backbone and positioned nitro functional groups was used to synthesize putative M-pro inhibitors. Two compounds, G1 and G4, exhibited anti-M-pro enzymatic activity in a dose-dependent manner, with the calculated IC50 values of 22.47 +/- 8.93 mu M and 24.04 +/- 0.67 mu M, respectively. The bio-layer interferometer measured real-time binding. The dissociation kinetics of G1/M-pro and G4/M-pro also showed similar equilibrium dissociation constants (K-D) of 2.60 x 10(-5) M and 2.55 x 10(-5) M, respectively, but exhibited distinct association/dissociation curves. Molecular docking of the two compounds revealed a similar binding cavity to the well-known M-pro inhibitor GC376, supporting a structure-function relationship. These findings may open a new avenue for developing new scaffolds for M-pro inhibition and advance anti-coronavirus drug research.