Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.

Ghosh, Arun K; Takayama, Jun; Rao, Kalapala Venkateswara; Ratia, Kiira; Chaudhuri, Rima; Mulhearn, Debbie C; Lee, Hyun; Nichols, Daniel B; Baliji, Surendranath; Baker, Susan C; Johnson, Michael E; Mesecar, Andrew D

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.