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Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity.
Gao, Shenghua; Sylvester, Katharina; Song, Letian; Claff, Tobias; Jing, Lanlan; Woodson, Molly; Weiße, Renato H; Cheng, Yusen; Schäkel, Laura; Petry, Marvin; Gütschow, Michael; Schiedel, Anke C; Sträter, Norbert; Kang, Dongwei; Xu, Shujing; Toth, Karoly; Tavis, John; Tollefson, Ann E; Müller, Christa E; Liu, Xinyong; Zhan, Peng.
  • Gao S; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Sylvester K; Shenzhen Research Institute of Shandong University, A301 Virtual University Park in South District of Shenzhen, Guangdong 518057, P. R. China.
  • Song L; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Claff T; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Jing L; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Woodson M; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Weiße RH; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63103, United States.
  • Cheng Y; Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri 63103, United States.
  • Schäkel L; Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.
  • Petry M; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Gütschow M; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Schiedel AC; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Sträter N; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Kang D; PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53113, Germany.
  • Xu S; Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.
  • Toth K; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Tavis J; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • Tollefson AE; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63103, United States.
  • Müller CE; Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri 63103, United States.
  • Liu X; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63103, United States.
  • Zhan P; Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri 63103, United States.
J Med Chem ; 65(19): 13343-13364, 2022 10 13.
Article in English | MEDLINE | ID: covidwho-2028635
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C, Chronic / COVID-19 Topics: Variants Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c01146

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C, Chronic / COVID-19 Topics: Variants Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c01146