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A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Author

Listed:
  • Shin-ichiro Hattori

    (National Center for Global Health and Medicine Research Institute)

  • Nobuyo Higashi-Kuwata

    (National Center for Global Health and Medicine Research Institute)

  • Hironori Hayashi

    (Tohoku University Hospital
    International Research Institute of Disaster Science, Tohoku University)

  • Srinivasa Rao Allu

    (Purdue University)

  • Jakka Raghavaiah

    (Purdue University)

  • Haydar Bulut

    (National Cancer Institute, National Institutes of Health)

  • Debananda Das

    (National Cancer Institute, National Institutes of Health)

  • Brandon J. Anson

    (Purdue University)

  • Emma K. Lendy

    (Purdue University)

  • Yuki Takamatsu

    (National Center for Global Health and Medicine Research Institute)

  • Nobutoki Takamune

    (Kumamoto University)

  • Naoki Kishimoto

    (Kumamoto University)

  • Kazutaka Murayama

    (Tohoku University)

  • Kazuya Hasegawa

    (Japan Synchrotron Radiation Research Institute)

  • Mi Li

    (National Cancer Institute
    Frederick National Laboratory for Cancer Research)

  • David A. Davis

    (National Cancer Institute, National Institutes of Health)

  • Eiichi N. Kodama

    (International Research Institute of Disaster Science, Tohoku University
    Tohoku University)

  • Robert Yarchoan

    (National Cancer Institute, National Institutes of Health)

  • Alexander Wlodawer

    (National Cancer Institute)

  • Shogo Misumi

    (Kumamoto University)

  • Andrew D. Mesecar

    (Purdue University)

  • Arun K. Ghosh

    (Purdue University)

  • Hiroaki Mitsuya

    (National Center for Global Health and Medicine Research Institute
    National Cancer Institute, National Institutes of Health
    Kumamoto University Hospital)

Abstract

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

Suggested Citation

  • Shin-ichiro Hattori & Nobuyo Higashi-Kuwata & Hironori Hayashi & Srinivasa Rao Allu & Jakka Raghavaiah & Haydar Bulut & Debananda Das & Brandon J. Anson & Emma K. Lendy & Yuki Takamatsu & Nobutoki Tak, 2021. "A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20900-6
    DOI: 10.1038/s41467-021-20900-6
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    Cited by:

    1. Daniel W. Kneller & Hui Li & Gwyndalyn Phillips & Kevin L. Weiss & Qiu Zhang & Mark A. Arnould & Colleen B. Jonsson & Surekha Surendranathan & Jyothi Parvathareddy & Matthew P. Blakeley & Leighton Coa, 2022. "Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Nobuyo Higashi-Kuwata & Kohei Tsuji & Hironori Hayashi & Haydar Bulut & Maki Kiso & Masaki Imai & Hiromi Ogata-Aoki & Takahiro Ishii & Takuya Kobayakawa & Kenta Nakano & Nobutoki Takamune & Naoki Kish, 2023. "Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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