Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity

  • J Med Chem. 2022 Oct 13;65(19):13343-13364. doi: 10.1021/acs.jmedchem.2c01146.
Shenghua Gao  1  2 ,  Katharina Sylvester  3 ,  Letian Song  1 ,  Tobias Claff  3 ,  Lanlan Jing  1 ,  Molly Woodson  4  5 ,  Renato H Weiße  6 ,  Yusen Cheng  1 ,  Laura Schäkel  3 ,  Marvin Petry  3 ,  Michael Gütschow  3 ,  Anke C Schiedel  3 ,  Norbert Sträter  6 ,  Dongwei Kang  1 ,  Shujing Xu  1 ,  Karoly Toth  4  5 ,  John Tavis  4  5 ,  Ann E Tollefson  4  5 ,  Christa E Müller  3 ,  Xinyong Liu  1 ,  Peng Zhan  1
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • 2. Shenzhen Research Institute of Shandong University, A301 Virtual University Park in South District of Shenzhen, Guangdong 518057, P. R. China.
  • 3. PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • 4. Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63103, United States.
  • 5. Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri 63103, United States.
  • 6. Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.
PMID: 36107752 DOI: 10.1021/acs.jmedchem.2c01146
Abstract

The continuous spread of SARS-CoV-2 calls for more direct-acting Antiviral agents to combat the highly infectious variants. The main protease (Mpro) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound GC-14 inhibits Mpro with high potency (IC50 = 0.40 μM) and displays excellent Antiviral activity (EC50 = 1.1 μM), being more potent than Remdesivir. Notably, GC-14 exhibits low cytotoxicity (CC50 > 100 μM) and excellent target selectivity for SARS-CoV-2 Mpro (IC50 > 50 μM for cathepsins B, F, K, L, and Caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.

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