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[摘要]：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 15h (enzyme IC50 = 0.56 mu M; antiviral EC50 = 9.1 mu M) and the corresponding (R)-Me 15g (IC50 = 0.32 mu M; antiviral EC50 = 9.1 mu M) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions. |
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