Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein−Ligand X-ray Structure and Biological Evaluation

TLDR

X‑ray crystal structures of SARS‑CoV PLpro bound to lead inhibitors reveal key ligand‑binding interactions. The study aims to design, synthesize, and evaluate novel SARS‑CoV PLpro inhibitors. High‑throughput screening identified lead 3 (6577871), which was optimized through structure‑activity studies to yield potent inhibitors, and crystal structures and docking models elucidate their binding. The most potent inhibitors, (S)-Me 15h and (R)-Me 15g, show IC50 values of 0.56 µM and 0.32 µM, respectively, and antiviral EC50 of 9.1 µM in Vero E6 cells.

Abstract

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 μM; antiviral EC50 = 9.1 μM) and the corresponding (R)-Me 15g (IC50 = 0.32 μM; antiviral EC50 = 9.1 μM) 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.