Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease

We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC50) = 0.46 µM; antiviral EC50) = 6 µ). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC50) = 1.3 µM) and the most potent SARS antiviral activity (EC50) = 5.2 µM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.

Arun K. Ghosh, Jun Takayama, Yoann Aubin, Kiira Ratia, Rima Chaudhuri, Yahira Baez, Katrina Sleeman, Melissa Coughlin, Daniel B. Nichols, Debbie C. Mulhearn, Bellur S. Prabhakar, Susan C. Baker, Michael E. Johnson, Andrew D. Mesecar
August 27, 2009
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