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

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 Takamune, Naoki Kishimoto, Kazutaka Murayama, Kazuya Hasegawa, Mi Li, David A. Davis, Eiichi N. Kodama, Robert Yarchoan, Alexander Wlodawer, Shogo Misumi, Andrew D. Mesecar, Arun K. Ghosh and Hiroaki Mitsuya ()
Additional contact information
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
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
David A. Davis: National Cancer Institute, National Institutes of Health
Eiichi N. Kodama: International Research Institute of Disaster Science, 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

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20900-6

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