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

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

  • Nat Commun. 2021 Jan 28;12(1):668. doi: 10.1038/s41467-021-20900-6.
Shin-Ichiro Hattori 1,  Nobuyo Higashi-Kuwata 1,  Hironori Hayashi 2 3,  Srinivasa Rao Allu 4,  Jakka Raghavaiah 4,  Haydar Bulut 5,  Debananda Das 5,  Brandon J Anson 6,  Emma K Lendy 6,  Yuki Takamatsu 1,  Nobutoki Takamune 7,  Naoki Kishimoto 8,  Kazutaka Murayama 9,  Kazuya Hasegawa 10,  Mi Li 11 12,  David A Davis 13,  Eiichi N Kodama 3 14,  Robert Yarchoan 13,  Alexander Wlodawer 11,  Shogo Misumi 8,  Andrew D Mesecar 6,  Arun K Ghosh 4,  Hiroaki Mitsuya 15 16 17
Affiliations

Affiliations

  • 1 Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 2 Department of Intelligent Network for Infection Control, Tohoku University Hospital, Miyagi, Japan.
  • 3 Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • 4 Department of Chemistry and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
  • 5 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 6 Department of Biochemistry and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
  • 7 Kumamoto Innovative Development Organization, Kumamoto University, Kumamoto, Japan.
  • 8 Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
  • 9 Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
  • 10 Protein Crystal Analysis Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
  • 11 Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, USA.
  • 12 Basic Science Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 13 Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 14 Department of Infectious Diseases, Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
  • 15 Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. [email protected].
  • 16 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 17 Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan. [email protected].
PMID: 33510133 DOI: 10.1038/s41467-021-20900-6
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.

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