Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors

  • J Med Chem. 2022 Dec 22;65(24):16902-16917. doi: 10.1021/acs.jmedchem.2c01716.
Shenghua Gao  1  2 ,  Letian Song  1 ,  Tobias Claff  3 ,  Molly Woodson  4  5 ,  Katharina Sylvester  3 ,  Lanlan Jing  1 ,  Renato H Weiße  6 ,  Yusen Cheng  1 ,  Norbert Sträter  6 ,  Laura Schäkel  3 ,  Michael Gütschow  3 ,  Bing Ye  1 ,  Mianling Yang  1 ,  Tao Zhang  7 ,  Dongwei Kang  1 ,  Karoly Toth  4  5 ,  John Tavis  4  5 ,  Ann E Tollefson  4  5 ,  Christa E Müller  3 ,  Peng Zhan  1 ,  Xinyong Liu  1
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan250012, China.
  • 2. Shenzhen Research Institute of Shandong University, A301 Virtual University Park in South District, Shenzhen518057, Guangdong, China.
  • 3. PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn53113, Germany.
  • 4. Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri63104, United States.
  • 5. Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri63104, United States.
  • 6. Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig04103, Germany.
  • 7. Shandong Qidu Pharmaceutical Research Institute, Yinfeng Biological City, Chunlan Road 1177, High Tech District, Ji'nan250101, China.
PMID: 36475694 DOI: 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.

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