3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents

  • J Med Chem. 2022 Feb 24;65(4):2926-2939. doi: 10.1021/acs.jmedchem.1c00665.
Sho Konno  1 ,  Kiyotaka Kobayashi  1 ,  Miki Senda  2 ,  Yuta Funai  3 ,  Yuta Seki  3 ,  Ikumi Tamai  3 ,  Laura Schäkel  4 ,  Kyousuke Sakata  5 ,  Thanigaimalai Pillaiyar  6 ,  Akihiro Taguchi  1 ,  Atsuhiko Taniguchi  1 ,  Michael Gütschow  4 ,  Christa E Müller  4 ,  Koh Takeuchi  7 ,  Mikako Hirohama  8 ,  Atsushi Kawaguchi  8 ,  Masaki Kojima  5 ,  Toshiya Senda  2 ,  Yoshiyuki Shirasaka  3 ,  Wataru Kamitani  9 ,  Yoshio Hayashi  1
Affiliations
  • 1. School of Pharmacy, Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • 2. Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
  • 3. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • 4. Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn 53121, Germany.
  • 5. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
  • 6. Pharmaceutical Institute, Pharmaceutical/Medicinal Chemistry, University of Tübingen, Tübingen 72076, Germany.
  • 7. Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Koto, Tokyo 135-0064, Japan.
  • 8. Faculty of Medicine, Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan.
  • 9. Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
PMID: 34313428 DOI: 10.1021/acs.jmedchem.1c00665
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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