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3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents.
Konno, Sho; Kobayashi, Kiyotaka; Senda, Miki; Funai, Yuta; Seki, Yuta; Tamai, Ikumi; Schäkel, Laura; Sakata, Kyousuke; Pillaiyar, Thanigaimalai; Taguchi, Akihiro; Taniguchi, Atsuhiko; Gütschow, Michael; Müller, Christa E; Takeuchi, Koh; Hirohama, Mikako; Kawaguchi, Atsushi; Kojima, Masaki; Senda, Toshiya; Shirasaka, Yoshiyuki; Kamitani, Wataru; Hayashi, Yoshio.
  • Konno S; School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • Kobayashi K; School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • Senda M; Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
  • Funai Y; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • Seki Y; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • Tamai I; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • Schäkel L; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn 53121, Germany.
  • Sakata K; School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
  • Pillaiyar T; Pharmaceutical Institute, Pharmaceutical/Medicinal Chemistry, University of Tübingen, Tübingen 72076, Germany.
  • Taguchi A; School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • Taniguchi A; School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • Gütschow M; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn 53121, Germany.
  • Müller CE; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn 53121, Germany.
  • Takeuchi K; Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Koto, Tokyo 135-0064, Japan.
  • Hirohama M; Faculty of Medicine, Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan.
  • Kawaguchi A; Faculty of Medicine, Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan.
  • Kojima M; School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
  • Senda T; Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
  • Shirasaka Y; Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • Kamitani W; Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
  • Hayashi Y; School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
J Med Chem ; 65(4): 2926-2939, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1327181
ABSTRACT
The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Peptidomimetics / Coronavirus 3C Proteases / SARS-CoV-2 / Ketones Limits: Animals / Humans / Male Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.1c00665

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Peptidomimetics / Coronavirus 3C Proteases / SARS-CoV-2 / Ketones Limits: Animals / Humans / Male Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.1c00665