Gao, S.; Song, L.; Claff, T.; Woodson, M.; Sylvester, K.; Jing, L.; Weisse, R.H.; Cheng, Y.; Straeter, N.; Schaekel, L.; Guetschow, M.; Ye, B.; Yang, M.; Zhang, T.; Kang, D.; Toth, K.; Tavis, J.; Tollefson, A.E.; Mueller, C.E.; Zhan, P.; Liu, X.: Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors. Journal of Medicinal Chemistry 65 (2022), p. 16902-16917
10.1021/acs.jmedchem.2c01716
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.