Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors
Shenghua Gao, Letian Song, Tobias Claff, Molly E. Woodson, Katharina Sylvester, Lanlan Jing, Renato H. Weiße, Yusen Cheng, Norbert Sträter, Laura Schäkel, Michael Gütschow, Bing Ye, Mianling Yang, Tao Zhang, Dongwei Kang, Károly Tóth, John E. Tavis, Ann E. Tollefson, Christa E. Müller, Peng Zhan, Xinyong Liu
Abstract
The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived Mpro inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, GD-9 was identified as the most potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 μM) and good antiviral potency against SARS-CoV-2 (EC50 = 2.64 μM), similar to that of remdesivir (EC50 = 2.27 μM). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.